Note: Descriptions are shown in the official language in which they were submitted.
~77~354
The present invention relates to novel biologically active tri-
cyclic compounds, to processes for the preparation of these compounds and to
the pharmaceutical application of these compounds. Particularly the invent-
ion :relates to novel benzo(b)bicyclo[3.3.1]nonenes of the general formula I:
and a pharmaceutically acceptable acid addition salt or nitrogen oxide there-
of, in which Rl and R2 stand for hydrogen, alkyl of 1 to 6 carbon atoms,
alkenyl of 2 to 6 carbon atoms, an acyl group or a phenylalkyl group in
which the alkyl moiety contains 1 to 6 carbon atoms and in which the phenyl
group is unsubstituted or substituted by one or more halogen atoms or lower
alkyl or alkoxy groups; R3 represents a free hydroxy group or an etherified
or esterified hydroxy group; X and Y are the same or different and represent
hydrogen or halogen atoms or alkyl or alkoxy groups of 1 to 6 carbon atoms,
nitro, trifluoromethyl or an acyloxy group, or Rl and R2 together with the
nitrogen atom represent a 5- or 6-membered heterocyclic ring.
The compounds of the general formula I have valuable biological
activities, particularly anorectic activity. Moreover the toxicity of the
compounds is very low.
The compounds of the present invention may be prepared accord-
ing to the usual methods described in the literature for similar compounds.
Thus this invention also relates to a process for the preparat-
ion of a benzo(b)bicyclo~3.3.1]nonene of the general formula I:
D
.. . .
.. . .. . . .. . .
. . . ... : .. . :- .
. . . . .
. -.
-
10779~;4
`:or a pharmaceutically acceptable acid addition salt or nitrogen oxide thereof,in which Rl and R2 stand for hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl
of 2 to 6 carbon atoms, an acyl group or a phenylalkyl group in which the
alkyl moiety contains 1 to 6 carbon atoms and in which the phenyl group is
unsubstituted or substituted by one or more halogen atoms or lower alkyl or
alkoxy groups; R3 represents a free hydroxy group OT an etherified or
esterified hydroxy group; X and Y are the same or different and represent
hydrogen or halogen atoms or alkyl or alkoxy groups of 1 to 6 carbon atoms,
nitro, trifluoromethyl or an acyloxy group which comprises either:
10 ~a) subjecting a ketone of the general formula II:
~ II
Y
, .
in which R3, X and Y are as previously defined to reductive amination, by
reducing the ketone of formula II in the presence of formamide,
N-alkylformamide or N,N-dialkylformamide or an amine of the general formula III:
,. ~Rl
HN III
\R2
wherein Rl and R2 have the same meanings as Rl and R2 with the exception of
an acyl group; or
(b) reducing an imine of the general formula IV:
y NR4 IV
., , ~
-27a-
.
. .
.
. ' ': - . -
: ' ' ~ . ~'
~ - \
1(~77954
in which X, Y and R3 are as previously defined and R4 stands for hydrogen,
- hydroxy, Cl 6 alkoxy, Cl 6 alkyl or a phenylalkyl group as defined aboYe; or
(c) reacting a reactive derivative of a hydroxyl compound of the
general formula V:
~_~ V
.
wherein X and Y are as previously defined and R5 represents an etherified or
esterified hydroxy group, with an amine of the general formula III as defined
above;
(d) when a compound of formula I is required in which R3 is a hydroxy
group hydrolysing a corresponding compound of formula I obtained in which R3
is an etherified or esterified hydroxy group;
~e) when a compound of formula I is required in which one or both of
Rl and R2 is a hydrogen atom hydrolysing a corresponding compound of formula I
obtained in which one or both of Rl and R2 is an acyl group;
(f) when a compound of formula I is required in which one or both of R
and R2 is an alkyl group of 1 to 6 carbon atoms, reducing a corresponding
compound of formula I obtained in which one or both of R1 and R2 is an alkanoyl
group of 1 to 6 carbon atoms;
. (g) wh~n a compound of formula I is required in which R3 is an esterified
r hydroxy group esterifying a corresponding compound of formula I obtained in
which R3 is a free hydroxy group;
: (h~ when a compound of formula I is required in which one or both of
Rl and R2 is an alkyl group of 1 to 6 carbon atoms or an alkenyl group of
~ -2b-
,
' ' ~,
, ~ ~, , ' .
- 1~77954
2 to 6 carbon atoms, alkylating a corresponding compound of formula I obtained
in which one or both of Rl and R2 is a hydrogen atom;
(i) when a compound of formula I is required in which one or both of
Rl and R2 is an acyl group, acylating a corresponding compound of formula I
in which one or both of Rl and R2 is a hydrogen atom; and where any one of
steps (a) to (i) can be followed by the additional step of converting a base
of formula I into a corresponding pharmaceutically acceptable acid addition
salt or nitrogen oxide.
A very convenient starting product in the synthesis of the
compounds of formula I is a substance of the general formula II:
-2c-
~(~779~4
in which X, Y and R3 have the meanings indicated previously.
These compounds II may be prepared in the usual manner starting
from an optionally substituted (X and/or Y) ~-tetralone. The tetralone in
question, which is commercially available or can be prepared in a convention-
al manner from commercially available tetralones, is treated with pyrroli-
dine affording the corresponding 2-(pyrrolidino)enamine. The enamine is
then converted with acrolein at low temperature into the corresponding
4-hydroxy-benzo(b)bicyclo[3.3.1]nonene-11-one. Alternatively the tetralone
in question may be reacted directly with acrolein at elevated temperature in
the presence of a tertiary amine such as trimethylamine to gi~e the corres-
ponding 4-hydroxy-benzo(b)bicyclo[3.3.1]nonene-11-one directly. The 4-
hydroxy group of this compound may then optionally be etherified or esteri-
fied. The condensation of the 2-tetralone enamine with acrolein can be
- carried out at preferred temperatures from -60 to +25C in a variety of
solventsJ but best conditions use a low temperature of -50 to -45 for the
addition of acrolein and allow the temperature to increase in a controlled
manner to ambient temperature over a period of up to 3 hours.
The alternative direct condensation of the op~ionally substituted
(X and/or Y)~ -tetralone with acrolein can be carried out at preferred
temperatures between +30 to +120 in a variety of solvents, but preferably
at the boiling point of the solvent used, in the presence of a tertiary
alkyl amine such as triethylamine or trimethylamine.
Starting from a compound of formula II the amines or amides of
~ the invention I can be prepared most conveniently and directly by a7 reductive amination.
This method involves a reaction of the starting ketone II with
formamide, N-alkylformamide or N,N-dialkylformamide or with an amine of
the general formula III:
' ' ' : ~ ~ .
' ' ~ ,:
. ~
.~ ~
1077~5~
/ i ~ III
\ R2- -
in which Rl and R2 have the same meanings as Rl and R2 with the exception of
an acyl group, in the presence of a suitable reducing agent.
A reducing agent, that is very suitable for this reaction, is
formic acid or a formic acid derivative such as a salt of formic acid and
the amine of formula III. In the latter case the separate addition of
the amine III is even superfluous. This reaction may be carried out at
elevated temperature, preferably in the range of 80-150C, and most con-
veniently at the boiling point of the reaction mixture.
10 Other suitable reducing agents in this reaction are metal
hydrides, such as lithiumaluminiumhydride, sodiumborohydride, sodiumtri-
methoxyborohydride and diisobutylaluminiumhydride; an alkalimetal,
preferably sodium, in an alcohol such as ethanol or isopropanol or hydrogen
in the presence of a suitable catalyst, such as Raney nickel, Pt, PtO2,
Pd/C etc. Some reducing agents may remove the ether- or the ester group,
optionally present at position 4, simultaneously to give compounds with a
hydroxy group at position 4, such as LiAlH4.
The compounds of the invention can further be obtained by
reduction of the imino moiety of a compound of the general formula IV:
~ NR4 IV
Y
in which X, Y and R3 have the meanings indicated above and R~ stands for
hydrogen5 hydroxy, alkoxy, alkyl (1-6 C) or an optionally substituted
aralkyl group.
, . .
.
~- 1077954
The compounds of formula IV may be prepared by reaction of the
ketone II with a primary amine of formula III (Rl = H) or with hydroxylamine
or a hydroxyl-amine-alkylether under alkaline conditions in the usual
manner for the preparation of imines or oximes.
The reduction of the imine IV is carried out under mild reaction
conditions by means of standard procedures for the reduction of an imino-
moiety. For example the reduction can be carried out by hydrogenation in
the presence of a suitable catalyst, such as Raney nickel, Pt or PtO2;
with a metalhydride, particularly complex- me~alhydrides derived from
aluminium or boron, such as lithium-aluminiumhydride, dissolved or sus-
pended in a suitable liquid, such as ether; with an alkalimetal preferably
sodium in a suitable liquid such as ether, benzene or alcohol; or with
sodiumamalgam or zinc dust in, for example, sodium hydroxide. The reaction
may result simultaneously in a splitting off of the 4-ether or the 4-ester
group to give the corresponding 4-alcohol, dependent upon the reducing
agent used.
A third method for the preparation of the compounds according to
the invention is starting from the hydroxyl compound of formula V:
,
X ~ OH V
., Y
in which X and Y have the meanings indicated above and R5 represents an
etherified or esterified hydroxy group.
` The compound V may be obtained by reduction of the corresponding
ketone II under mild conditions so that the R5 group present is not
removed. A suitable reducing agent in this respect is sodiumborohydride.
The hydroxyl compound V can be converted into the corresponding
amine in various ways. For example, the
.
.
'. ' ' .
,' ' ~ ' :
,
~(~77~5~
said hydroxyl group may be converted into a suitable alkyl- or aryl-
sulfonyloxy group (leaving group), such as a mesyloxy group, a tosyloxy
group, a p-bromophenylsulfonyloxy group, a p-chlorophenylsulfonyloxy
group, a p-nitrophenylsulfonyloxy group, etc. and then be reacted with an
amine according to the general formula III.
Instead of the conversion of the hydroxyl group into the above-
mentioned alkyl- or arylsulfonyloxy group, the hydroxyl group may also be
halogenated, for example with PC15, PBr3, SOC12, etc., and then be con-
verted into the desired compound I by reaction with the amine III.
; 10 The conversions from a hydroxyl group into an amino group are
well-known and described in any chemical textbook.
The aforesaid primary reactions for the preparation of the
compounds of the invention (I) may be followed by additional reactions
for the conversion of a compound of formula I into a salt or nitrogenoxide
thereof, or for the conversion from one compound of the invention into
, another compound of the invention.
So, it is possible to modify a substituent present at the
phenylnucleus into another substituent within the definition of X and/or
~, Y. For example, a methoxy group may be converted into a hydroxyl group,
e.g. by treating with fused pyridine. HCl in the absence of a solvent or
by hydrolysis with HBr; a hydroxy group can be converted into an alkoxy
' group, halogen, or an acyloxy group in a conventional manner.
. The amines of the invention, unsubstituted or mono-substituted
at the nitrogen atom (Rl and/or R2 is hydrogen) may be ~ar)alkyl-
., .
- 6 -
, ~ ' , .' : .
" ' : .
~C~779S4
ated in the usual manner, for example by reacting the compound with an
(ar)alkylhalide, or by acylating the compound followed by reduction of
the carbonyl group.
For the introduction of methyl-groups at the nitrogen atom the
well-known procedure of Eschweiler-Clarke (reaction with formaldehyde +
formic acid) or the reaction with formaldehyde or haloformic esters,
followed by reduction with e.g. sodium-cyanoborohydride is to be preferred.
An N-acyl derivative of the compounds according to the invention,
may preferably be obtained by acylating a compound I, in which at least one
of the groups Rl or R2 is hydrogen, in the usual manner using an anhydri,de
or acid halide.
Such acylations, carried out on the 4-alcohol derivative
I(in which R3 = OH), will result in simultaneous esterification of the
4-hydroxy group.
Where an N-formyl derivative is obtained directly from one of
the aforesaid primary reactions, the amide in question may by hydrolysed
using e.g. potassium or sodiumhydroxide to obtain the primary amine I.
Such hydrolysis may result in a simultaneous hydrolysis of the 4-ester
group to the 4-alcohol. For example, the reductive amination, in which
the ketone II is reacted with formamide in the presence of formic acid
(Leuckart-Wallach reaction) gives in first instance the N-formyl de-
rivative I, which derivative can be hydrolysed to the primary amine I,
or reduced to the corresponding N-methyl compound I.
An O-acyl derivative (R3 = acyloxy) of the compounds according
to the invention in which the primary or secondary amine group remains
unreacted may be prepared by treating the amine I, in which R3 = OH, with
an acylating agent such as an acid halide or anhydride in the presence of a
strong acid such as trifluoroacetic acid or perchloric acid.
All these additional conversions which might be carried out
'' ' , --, - : :
: :
:
,
_ . . ~ !
1(1 77~54
after the aforesaid primary reactions are standard procedures well-known
in the art. As far as specific reagents have been mentioned in these
additional conversions, it may be understood that these reagents can be
replaced by other reagents, well-known in organic chemistry, having a
similar effect as the specific reagents described.
The preparation of the ketone II used as starting product in the
present synthesis to a compound of formula I results in a mixture consisting
, of two enantiomers of formula II in which the 4-alcohol or ester group is
in the exo-position, and two enantiomers of formula II in which the 4-alcohol
or ester group is in the endo-position. The exo-enantiomers can be separated
,~ from the endo-enantiomers by crystallisation or chromatography. Each of theracemic mixtures II thus obtained may be processed as such and then optionally
;;
resolved after conversion to a racemic compound I or may be resolved and then
be processed into an optically active end product according to formula I.
The replacement of the oxo-group at position II of the ketone II
~ with an amino group or the reduction of the imine IV introduces another
A asymmetric centre resulting in the mixture of two diastereomers I, in which- the amino group is present in syn- or anti-position with respect to the
benzene ring. The separate diastereomeric forms can be isolated from the
mixture in the usual manner, for example by column chromatography, preparative
thin-layer chromatography and/or fractional crystallisation.
The diastereomers, enantiomers and mixtures thereof of formula I
as well as their preparation are also encompassed by this invention.
The novel compounds of formula I may be isolated from the reaction
` mixture in the form of a pharmaceutically acceptable salt, dependent upon the
~ conditions in which the reaction is carried out. The pharmaceutically accept-
: able salts may also be obtained by treating the free base I with an organic or
: ~ .
-- 8 --
lQ77954
inorganic acid, such as HCl, HBr, Hl, H2S04, H3P04, acetic acid, propionic
acid, glycollic acid, maleic acid, malonic acid, succinic acid, tartaric
acid, citric acid, benzoic acid, ascorbic acid, etc.
The term "alkyl" used in the definition of X, Y, Rl and R2 of the
general formula I means a saturated branched or unbranched hydrocarbon
radical with 1-6 carbon atoms, such as methyl, ethyl, n.propyl, n.butyl,
cyclopropyl, cyclopropylmethyl, isopropyl, isobutyl, t.butyl, n.pentyl, iso-
pentyl, cyclopentyl and hexyl. The same applies to the alkyl group present
in the term "alkoxy" used in the definition of X and Y.
The term "alkenyl" used in the definition of Rl and R2 of the
general formula I means an unsaturated branched or unbranched hydrocarbon
radical with 2-6 carbon atoms such as vinyl, allyl and 3-methyl-but-2-enyl.
By "halogen" is preferably meant chlorine or bromine.
By an "aralkyl~group", mentioned in the definition of Rl and R2,
is meant an alkyl group with 1-6 carbon atoms, substituted with at least
one aromatic group. Preferably a phenylalkyl group is meant, in which the
alkyl group has 1-4 carbon atoms and in which the phenyl group may be
substituted by one or more halogen, lower alkyl or alkoxy groups (1-4 C),
such as benzyl, phenyl-ethyl, phenylpropyl, phenylbutyl, l-methyl-l-phenyl-
ethyl, o-, m-, or p-anisyl, o-, m- or p-chloro-benzyl, veratryl, o-, m- or
p-methyl-phenethyl or o-, m- or p-hydroxyphenethyl.
An "acyl group" mentioned in the definition of Rl, and R2 means
a group derived from an aliphatic, araliphatic or aromatic carboxylic acid.
The aliphatic carboxylic acids cover acids with 1-18 carbon atoms, in-
cluding a carbocyclic ring, and particularly those with 1-8 carbon atoms,
such as acetic acid, propionic acid, butyric acid, iso-butyric acid, valeric
acid, hexanoic acid, heptanoic acld, trimethyl-acetic acid, cyclopentane-
or cyclohexane-carboxylic acid. The araliphatic or aromatic carboxylic
~, acids cover unsubstituted as well as substituted araliphatic
.,
_ 9 _
.. . . . . . .
.
.
.
` 1~77954
or aromatic carboxylic acids with 1-18 carbon atoms, especially the
optionally substituted phenyl-carboxylic acids, and optionally substituted
phenylalkyl-carboxylic acids) in which the alkyl group contains 1-4 carbon
atoms and may be saturated as well as unsaturated, such as benzoic acid,
o-, m- or p-toluic acid, o- or p-chlorobenzoic acid, p-methoxybenzoic acid,
phenyl acetic acid, phenylpropionic acid, cinnamic acid, phenylbutyric acid,
p-methylphenyl acetic acid, p-nitrobenzoic acid, etc.
The acyl group in the term "acyloxy" or "esterified hydroxy group"
used in the definitions of X, Y and R3 has a similar meaning.
The etherified hydroxy group mentioned in the definition of R3 is
an aliphatic (1-6 C) ether, a cycloaliphatic (5-10 C) ether, an aromatic
ether, preferably a phenyl-ether, an araliphatic ether, preferably a phenyl-
alkylether, or a heterocyclic ether such as a tetrahydropyranylether. The
phenyl moiety in the phenyl or phenylalkyl ethers may be substituted by
alkyl (1-4 C), alkoxy ~1-4 C), halogen or nitro.
The heterocyclic five- or six-membered rings, as mentioned in the
definition of Rl and R2 (together with the nitrogen atom), are derived from
5- or 6-membered cyclic amines of formula III, such as pyrrole, pyrrolidine,
pyrroline, piperidine, piperazine, imidazole or morpholine.
The nitrogen oxides of the compounds of the invention are
prepared by oxidising a compound I with H2O2 or a peracid.
The novel compounds according to this invention as well as the
pharmaceutically acceptable salts thereof have, as already said, valuable
anorectic activities. A long term oral administration of the compounds I
did not evoke tolerance to the anorectic effect. The compounds I,
especially the ll-syn isomers I, show moreover a moderate
- 10 -
1~77954
.,
anti-inflammatory activity. Purthermore an antidepressant effect is
indicated by the overall pharmacological profile of the compounds of the
invention.
The compounds of the invention may be administered orally,
parenterally and locally (the latter substantially for anti-inflammatory
purposes), in a daily dosage of from 0.005 to 50 mg, preferably 0.01-10
mg, per kg body weight.
Mixed with suitable auxiliaries the compounds I may be compressed
into solid dosage units, such as pills, tablets and coated tablets or be
processed into capsules.
By means of suitable liquids the compounds I can also be applied
as an injection preparation in the form of solutions, suspensions or
emulsions.
For topical administration the compounds may also be processed
into a cream or ointment.
Preferred compounds of the invention are compounds of formula I,
in which Rl and R2 are hydrogen or methyl and/or the benzonucleus has been
substituted by one or two halogen and/or R3 stands for hydrogen, a lower
aliphatic acyl group (1-8 C) or a lower araliphatic acyl group, such as
benzOyl~
.'
,~.
.. ... .
., - 11 -
.,.
- , . . . . . .:
, : , : .
: .
~:
, ' '' ''' ' ~ ~ ' .': '
.. . . . .
: 1~77954
STARTING PRODUCTS
The preparation of 4-exo and 4-endo-hydroxy as well as 4-exo- and
4-endo-benzyloxy-8-chloro-benzo(b)bicyclo[3.3.1] nonen-ll-one is described
starting from 6-chloro-2-tetralone. Other starting products according to
formula II are prepared in a similar manner.
A. 6-chloro-2- tetralone pyrrolidine enamine
A solut;on of 6-chloro-2-tetralone (260 g) in benzene (1.5 1) and
pyrrolidine (208 ml) was refluxed under nitrogen for 2.5 h using a
Dean and Stark water separator to collect the water formed. The
reaction mixture was evaporated to dryness under reduced pressure,
venting with nitrogen at the end of the distillation. The residue
was triturated with hexane to give 6-chloro-2-tetralone pyrrolidine-
enamine (276 g; 82%) m.p. 121-122C.
B. 8-chloro-4-hydroxy=benzo(b)bicyclo[3.3.1]nonen-11-one
B.l. 6-chloro-2-tetralone pyrrolidine enamine (390 g) was added
portionwise during 10 min. to a stirred solution of acrolein (214 ml)
in methylene dichloride (3.0 1) cooled to -50 to -55C. The reaction
mixture was stirred for 30 min. at -50 to -55C, then the temperature
was allowed to rise to +5 during 3 h. Water (420 ml) was added,
followed by 5N hydrochloric acid (400 ml) and the resulting biphase
mixture was stirred at room temperature for 2 h and set aside overnight.
The layers were separated and the aqueous layer was extracted with
methylene dichloride. The methylene dichloride extracts were washed
with lN hydrochloric acid, aqueous brine, dried and evaporated to
dryness to give a mixture (approx. 60:40) of 8-chloro-4-exo- and 8-
chloro-4-endo-hydroxy-benzo(b)bicyclo~3.3.1]nonen-11-one as an oil
(371 g).
B.2. Acrolein (389 ml) was added to a stirred solution of 6-chloro-
- 12 -
- ,.
- .
- , : . - :
: , '. : '
` 10~7954
2-tetralone (738 g) in tetrahydrofuran (738 ml) and triethylamine
(738 ml) under a nitrogen atmosphere and the mixture was heated
under reflux for 2.5 h. The solvents were distilled off in vacuo
and the triethylamine finally removed by azeotropic distillation
with toluene (2.75 1) in portions (250 ml).
; The crude ketol mixture (810 g) was dissolved in toluene,
filtered through alumina, and the eluate evaporated to give a
mixture (approx. 60:40) of 8-chloro-4-exo- and 8-chloro-4-endo-
hydroxy-benzo(b)bicyclo[3.3.1]nonen-11-one as an oil (792 g).
C 4-Exo- and 4-endo-benzoyloxy-8-chloro-benzo(b)bicyclo[3.3.1]nonen-11-one
.
A solution of 8-chloro-4-exo- and 8-chloro-4-endo-hydroxy-benzo(b)
; bicyclo[3.3.1]nonen-11-one (52 g) in pyridine (104 ml) was cooled with
stirring to 2 and benzoyl chloride (30.5 ml) was added dropwise, keeping
the temperature below 10C. Stirring was continued at 5 to 10C for
3.5 h. Water was added to the cooled, stirred mixture to precipitate the
product, which was dissolved in methylene dichloride and washed with 2N
hydrochloric acid, water to pH 7, dried, and evaporated to give a mixture
of 4-exo- and 4-endo-benzoyloxy-8-chloro-benzo(b)bicyclo[3.3.1]nonen-11-
one (62 g) (approx. 60:40).
" 20 A solution of the product in methylene dichloride was filtered through
a column of alumina, concentrated, and the residue crystallised from
methylene dichloride-cyclo-hexane to give pure 4-exo-benzoyloxy-8-chloro-
benzo(b)bicyclo[3.3.1]nonen-11-one (26 g) m.p. 184-186C. The mother
liquor was chromatographed over alumina to give a further quantity (7.5 g)
of pure 4-exo-benzoyloxy-8-chloro-benzo(b)bicyclo[3.3.1]nonen-11-one and
~ pure 4-endo-benzoyloxy-8-chloro-benzo(b)bicyclo[3.3.1]nonen-11-one (18.5
.~
g) m.p. 120-122C.
, "
- 13 -
.
:' ' . ' :,
:
1(~77954
EXAMPLE I
4-exo-Benzoyloxy-8-chloro-11-anti-formamido-~enzo(b)bicyclo[3.3.1]nonene.
A suspension of 4-exo-benzoyloxy-8-chloro-benzo(b)bicyclo[3.3.1]nonen-11-
one (33.5 g) in a mixture of formamide (134 ml) and formic acid (67 ml) is
boiled under reflux for 2.5 h. After cooling the mixture, water is added
and the solid is filtered off, washed with water and dried (32.5 g). The
product is crystallised from methylene dichloride/methanol giving 4-exo-
benzoyloxy-8-chloro-11-anti-formamido-benzo(b)bicyclo~3.3.1]nonene as prisms
(28.5 g) m.p. 224-226C.
EXA~lPLE II
4-endo-Benzoyloxy-8-chloro-11-formamido-benzo(b)bicyclo[3.3.1]nonene.
A stirred suspension of 4-endo-benzoyloxy-8-chloro-benzo(b)bicyclo[3.3.1]
nonen-ll-one (18.5 g) in a mixture of formamide (74 ml) and formic acid
(37 ml) is heated under reflux for 2.5 h. After cooling the mixture, water
is added and the gum is dissolved in methylene dichloride, washed neutral
and chromatographed over silica gel to give 4-endo-benzoyloxy-8-chloro-
ll-anti-formamido-benzo(b)bicyclo[3.3.1]nonene (7 g) as prisms m.p. 150-152
and 4-endo-benzoyloxy-8-chloro-11-synformamido-benzo(b)bicyclo[3.3.1]nonene
as an almost colourless gum (3.5 g).
EXAMPLE III
4-Acetoxy- or 4-benzoyloxy-11-formamido-substituted benzo(b)bicyclo[3.3.1]
.
nonene
Starting from the desired 4-acyloxy-benzo(b)bicyclo[3.3.1]nonen-11-one
compound, unsubstituted or substituted at the benzo ring, the following
ll-formamido compounds are prepared in the same manner as described in
Examples I and II.
4-exo-Acetoxy-8-methoxy-11-anti-formamido-benzo(b)bicyclo[3.3.1]nonene,
m.p. 172-173C;
- 14 -
.
. ~: . - - ,, : .
- , . -
. . : : ' :
~ 77954
4-exo-Benzoyloxy-8-bromo-ll-antl-formamido-benzo(b)bicyclo [3.3.1]nonene,
m.p. 229-230C;
- 14a -
- - . ~, : :
'
.
. . . :
. ~
'` 10779S4
:
4-endo-Benzoyloxy-8-bromo-11-anti-formamido-benzo(b)bicyclo[3.3.1]nonene, (oil)
4-exo-Benzoyloxy-8,9-dichloro~ anti-formamido-benzo(b)bicyclo[3.3.1]nonene,
m.p. 242-243C;
4-endo-p.nitrobenzoyloxy-9-chloro-11-anti-formamido-benzo~b)bicyclo[3.3.1]
nonene, m.p. 142-149C;
4-endo-p.nitrobenzoyloxy-9-chloro-11-syn-formamido-benzo~b)bicyclo[3.3.1]nonene,
m.p. 197-200C;
4-exo-Acetoxy-ll-anti-formamido-benzo(b)bicyclo[3.3.1]nonene, m.p. 121-122C;
4-exo-Acetoxy-ll-syn-formamido-benzo(b)-bicyclo[3.3.1]nonene, m.p. 182-184C;
4-exo-Acetoxy-8-chloro-9-CF3-11-anti-formamido-benzo(b)bicyclo[3.3.1]nonene.
EXAMPLE IV
4-e~ ~y~ y _____ oro-11-anti-amino-ben ~ l33 ~
A suspension of 4-exo-benzoyloxy-8-chloro-11-anti-formamido-benzo(b)bicyclo-
[3.3.1]nonene (8 g)in ethanol (80 ml) and lOM potassium hydroxide solution
(14 ml) is heated under reflux for 4 h during which time a solution is
obtained. After cooling, aqueous brine is added to precipitate the amine
which is filtered off, washed with water and dried to give 4-exo-hydroxy-8-
chloro-ll-anti-amino-benzo(b)bicyclo[3.3.1]nonene as prisms (5 g). The amine
~4.3 g) is dissolved in ethanol/toluene and converted to the hydrochloride
'~ 20 by addition of a solution of hydrogen chloride gas in ether. Crystallisation
from isopropanol gives pure 4-exo-hydroxy-8-chloro-11-anti-amino-benzo(b)-
bicyclo[3.3.1]nonene hydrochloride (4.1 g) m.p. 182-194 (decomp.).
In the same manner are prepared:
4-exo-hydroxy-8-methoxy-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene.HCl~
identical with the product obtained in Example XlX
4-exo~hydroxy-8-bromo-11-anti-amino-benzo(b)bicyclo[3~3.1]nonene.HCl.
~ ~ -15-
. ~ .
,
.
,
- , . ..
, ' ' , ' ' ,
1~77gS4
4-endo-hydroxy-8-bromo-11-anti-amino-benzo(b)bicyclo[3.3.1]noneneOHCl.
4-exo-hydroxy-8,9-dichloro-11-anti-amino-benzo~b)bicyclo[3.3.1]nonene.HCl,
identical with the product obtained in Example XlXo
4-endo-hydroxy-8,9-dichloro-11-anti-amino-benzo(b)bicyclo[3.3O1]nonene.HCl.
4-endo-hydroxy-8,9-dichloro-11-syn-amino-benzo(b)bicyclo[3O3O1]nonene.HCl.
4-exo-hydroxy-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene.HCl, identical with
the product obtained in Example XlX;
4-exo-hydroxy-8-methyl-11-anti-amino-benzo(b)bicyclo[3.3.1]noneneOHC10
4-exo-hydroxy-8-chloro-9-CF3-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene oHCl
4-exo-hydroxy-8-nitro-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene. HC 1
: EXAMPLE V
4-hydroxy-8-chloro-11-methylamino-benzo(b)bicyclo~3.3.11nonene HCl
A solution of 4-exo-benzoyloxy-8-chloro-11-anti-formamido-benzo(b)bicyclo-
~3.3.1]nonene (7O25 g) in dry tetrahydrofuran ~110 ml) is added dropwise
to a stirred suspension of lithium aluminium hydride (2.0 g) in dry
tetrahydrofuran ~40 ml) and the mixture is stirred under reflux for 5 h.
After the addition of water, the inorganic solids are filtered off. The
filtrate is concentrated, toluene added and the solution is evaporated in
vacuo to give 4-exo-hydroxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo[3.3.1]-nonene ~6.5 g) as a gum, which is dissolved in methylene dichloride and
converted to the hydrochloride by addition of a saturated solution of hydrogen
chloride gas in ether. Crystallisation from methylene dichloride/ethyl
acetate gives pure 4-exo-hydroxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo-
~3.3.1]nonene hydrochloride as prisms (4.2 g) mOp.~'190C ~decomp.).
.
~ -16-
..
. . . .
,' :
.
1~77954
In the same manner 4-endo-hydroxy-8-chloro~ anti-methylamino-
benzo~b)bicyclo[3.3.1]nonene hydrochloride, m.p. 262-268 and 4-endo-hydroxy-
8-chloro-11-syn-methylamino-benzo~b)bicyclo[3.3.1]nonene hydrochloride are
prepared starting from the appropriate 4-endo-acetoxy- or benzoyloxy-ll-
formamido compounds.
EXAMPLE VI
4-Hydroxy-ll-methylamino-substituted-benzo~b)bicyclo[3.3.1]nonene.
Starting from the desired 4-acetoxy- or 4-benzoyloxy-11-formamido-benzo(b)
- bicyclo[3.3.1]nonene, unsubstituted at the phenyl ring, or substituted at the
phenyl ring with 9-chloro, 8-methoxy, 8-hydroxy, 8-methyl, 8,9-dichloro or
8-chloro-9-nitro respectively, the following ll-methylamino compounds are
prepared in the same manner as described in Example V.
4-exo-Hydroxy-ll-anti-methylamino-benzo~b)bicyclo[3.3.1]nonene.
4-endo-Hydroxy-ll-anti-methylamino-benzo~b)bicyclo[3.3.1]nonene.
4-exo-Hydroxy-8-methoxy-11-anti-methylamino-benzo(b)bicyclo[3.3.1]nonene.
4-endo-Hydroxy-8-methoxy-11-anti-methylamino-benzo~b)bicyclo[3.3.1]nonene.
4-endo-Hydroxy-8-methoxy-11-syn-methylamino-benzo~b)bicyclo[3.3.1]nonene.
4~endo),8-Dihydroxy-ll-anti-methylamino-benzo~b)bicyclo[3.3.1]nonene.
4-exo-Hydroxy-8-methyl-11-anti-methylamino-benzo(b)bicyclo[3.3.1]nonene.
4-eXo-Hydroxy-8,9-dichloro-ll-anti-mèthylamino-benzo(b)bicyclo[3.3.1]nonene.
4-exo-Hydroxy- 9-chloro- 11-anti-methylamino-benzo~b)bicyclo[3.3.1]nonene.
4-exo-Hydroxy-8-chloro-9-nitro-11-anti-methylamino-benzo~b)bicyclo[3.3.1]
nonene.
- ' ', - . . .
. .
. . .
. . . . ..
' ~
, :..
779S4
EXAMPLE VII
8-Bromo-4-exo-hydroxy~ anti-methylamino-benzo~b)bicyclo[3.3.1]nonene.HCl.
A mixture of 4-exo-benzoyloxy-8-bromo-benzo(b)bicyclo[3.3.1]nonen-11-one
(6 g) and N-methyl-formamide ~18 ml) in formic acid (9 ml) is boiled under
reflux for 3 h. The reaction mixture is cooled to room temperature, diluted
with water and treated with 2N sodium hydroxide solution to give a yellow
gum, which is extracted with methylene dichloride. The methylene dichloride
extracts were washed with water, dried and evaporated to give a brown gum
(5.97 g). The gum (5.97 g) is dissolved in ethanol (120 ml) and heated
under reflux with lON potassium hydroxide solution (12 ml) for 27 h. The
reaction mixture is cooled to room temperature, diluted with brine and
extracted with methylene dichloride. The methylene dichloride extracts are
washed with water, dried and evaporated in vacuo to give the crude amine as
an orange gum (4.23 g), which is dissolved in methylene dichloride and con-
verted to the hydrochloride by addition of a solution of hydrogen chloride
gas in ether. Crystallisation from methylene chloride and from methanol-
ether gives pure 4-exo-hydroxy-8-bromo-11-anti-methylamino-benzo(b)bicyclo
[3.3.1]nonene hydrochloride as colourless crystals (1.30 g), m.p. 264-270C.
EXAMPLE VIII
4-exo-acetoxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo[3.3.1]nonene.HCl.
A solution of 4-exo-hydroxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo
[3.3.1]nonene (4 g) in a mixture of perchloric acid (6 ml), acetic anhydride
(10 ml) and glacial acetic acid (20 ml) is set aside for 1 h. The solution
is poured into ice-water, solid potassium carbonate added until alkaline and
the product is extracted into methylene dichloride, washed to neutrality,
dried and evaporated to dryness to give 4-exo-acetoxy-8-chloro-11-anti-
methylamino-benzo(b)bicyclo[3.3.1]nonene (4.7 g) as a gum. The product is dis-
- 18 -
. .
7795~
solved in methylene dichloride and filtered through acid-washed alumina.
The eluate is concentrated and a saturated solution of hydrogen chloride gas
in ether is added to precipitate the hydrochloride (3.65 g), crystallisation
of which from methanol-ethyl acetate yields 4-exo-acetoxy-8-chloro-11-anti-
methylamino-benzo(b)bicyclo[3.3.1]nonene hydrochloride as prisms (3.1 g) m.p.
?56C.
In a similar manner the following compounds are prepared:
4-exo-acetoxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene.HCl,
m.p. 256C;
4-endo-acetoxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene.HCl,
m.p. 259-263C;
4-exo-acetoxy-8,9-dichloro-11-anti-methylamino-benzo(b)bicyclo[3.3.1]nonene.
HCl, m.p. 247-253C.
EXAMPLE IX
4-exo-benzoyloxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene.HCl.
Benzoyl chloride (2.3 ml) is added dropwise to a solution of 4-exo-hydroxy-
8-chloro-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene (4.8 g) in trifluoro-
acetic acid (20 ml) and the mixture is stirred at room temperature for 7 h.
then poured on to ice. Solid sodium carbonate is added until alkaline and
the product is extracted into ethyl acetate. The extract is washed with
2 M NaOH, and water to pH 7, then dried and evaporated to give a gum
(5.0 g). Crystallisation from ether gives 4-exo-benzoyloxy-8-chloro-11-
anti-amino-benzo(b)bicyclo[3.3.1]nonene (3.2 g).
Treatment of the crystalline product in methylene dichloride with
a saturated solution of hydrogen chloride gas in ether gives 4-exo-benzoyl-
oxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene.HCl, m.p. 213-220C.
_ 19 -
'' . ~ ~ . .: ~
: . . , ' : . ~ : - .
'' ' ' ': ' ,: ' ~
`
1077954
EXAMPLE X
~ y treatment of the 4-hydroxy-ll-amino- and ll-methylamino compounds
with the appropriate acylhalide, the following compounds are prepared in a
manner, similar to that described in example IX.
4-exo-benzoyloxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo[3.3.1]nonene.
I~Cl
4-exo(2,2-dimethylpropionyloxy)-8-chloro-ll-anti-amino-benzo(b)bicyclo
[3.3.1]nonene.HCl.
4-endo-benzoyloxy-8-methoxy-11-syn-methylamino-benzo(b)bicyclo[3.3.1]nonene.
HCl.
4-exo-benzoyloxy-8-bromo-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene.HCl.
EXAMPLE XI
4-exo-hydroxy-8,9-dichloro-11-anti-dimethylamino-benzo~b)bicyclo[3.3.1]
nonene.HCl
A solution of 4-exo-hydroxy-8,9-dichloro-ll-anti-amino-benzo(b)
bicyclo[3.3.1]nonene (16.6 g) in a mixture of formic acid (16.6 ml) and
formalin (15.5 ml) is boiled under reflux for 2 h., diluted with water and
an excess of potassium hydrogen carbonate solution and extracted with
methylene dichloride. The extract is washed neutral with water, dried and
evaporated and the residue crystallised from ether to give 4-exo-hydroxy-
8,9-dichloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene (16.2 g),
m.p. 133.5-135. The product is dissolved in methylene chloride and treated
with a solution of hydrogen chloride in ether to give the hydrochloride,
m.p. 248-273C.
The same compound is obtained by refluxing a mixture of 4-exo-
benzoyloxy-8,9-dichloro-benzo(b)bicyclo[3.3.1]nonen-11-one and dimethyl-
formamide in formic acid in a similar manner as described in Example VII.
- 20 -
1~77gS4
EXAMPLE XII
4-Hydroxy~ dimethylamino-benzo(b~bicyclo[3.3.1]nonenes.
Starting from the desired 4-hydroxy-11-amino-benzo(b)bicyclo
[3.3.1lnonene, unsubstituted at the phenyl ring, or substituted at the phenyl
ring with 8,9-dichloro, 8-methoxy, 8-hydroxy, 9-chloro, 8-chloro and 8,10-
dichloro respectively, the ollowing ll-dimethylamino compounds are prepared
in the manner described above.
4-exo-hydroxy-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl,
4-exo-hydroxy-8-methoxy-11-anti-dimethylamino-benzo(b)bicycle[3.3.1]nonene.
HCl,
4-endo-hydroxy-8,9-dichloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]
nonene.HCl,
4-endo-hydroxy-8,9-dichloro-11-syn-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.
HCl,
4(exo),8-dihydroxy-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl,
4-exo-hydroxy-8-chloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl,
4-endo-hydroxy-8-chloro-11-anti-dimethylamino-benzo(b)bicycloE3.3.1]nonene.
HCl,
4-endo-hydroxy-8-chloro-11-syn-dimethylamino-benzo(b)bicyclo[3.3,1]nonene.HCl,
4-exo-hydroxy-9-chloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl,
4-exo-hydroxy-8,10-dichloro-11-syn-dimethylamino-benzo(b)bicyclo[3.3.1]
nonene.HCl,
E MPLE XIII
4-exo-Acetoxy-8,9-dichloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]
nonene.HCl.
Acetylation of 4-exo-hydroxy-8,9-dichloro-11-anti-dimethylamino-
benzo(b)bicyclo[3.3.1]nonene (4.0 g) with acetic anhydride (8 ml) and pyridine
(8 ml) at room temperature gives 4-exo-acetoxy-8,9-dichloro-11-anti-
- 21 -
. ' ' . ' '. ..
- ~ .
. . , . ~ - .
.
~
1~377954
dimethylamino-benzo(b)bicyclo[3.3.1]nonene (4.4 g), m.p. 122.5-124. This
is dissolved in methylene chloride and treated with a solution of hydrogen
chloride in ether to give the hydrochloride, m.p. 234-27~.
The following compounds are acylated in a similar manner
4-endo-acetoxy-8,9-dichloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]
nonene.HCl,
4-exo-phenylacetoxy-8,9-dichloro-11-anti-dimethylamino-benzo(b~bicyclo[3.3.1]
nonene . HC 1,
4-exo-benzoyloxy-8,9-dichloro-11-anti-dimethylamino-benzo(b)bicyclol3.3.1]
nonene.HCl,
4-exo-heptanoyloxy-8,9-dichloro-11-anti-dimethylamino-benzo(b)bicyclol3.3.1]
nonene.HCl,
4-exo-(2,2-dimethylpropionyloxy)-8,9-dichloro-11-anti-dimethylamino-benzo(b)
bicyclo[3.3.1]nonene.HCl.
EXAMPLE XIV
Esters of 4-hydroxy-11-dimethylam no-benzo(b)bicyclo[3.3.1]nonene derivatives.
Starting from the desired 4-hydroxy-11-dimethylamino-benzo(b)
bicyclo[3.3.1]nonene, unsubstituted at the phenyl ring, or substituted at the
phenyl ring with 8-methoxy, 8-bromo, 8-chloro and 8-methyl respectively, the
following esters of 4-hydroxy-11-dimethylamino compounds are prepared in
the manner described above.
4-exo-acetoxy-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1] nonene.HCl.
4-exo-benzoyloxy-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl.
4-exo-(2,2-dimethylpropionyloxy)-11-anti-dimethylamino-benzo(b)bicyclo
13.3.1]nonene.HCl.
4-exo-(1-phenylpropionyloxy)-11-anti-dimethylamino-benzo(b)bicyclo~3.3.1]
nonenc.HCl.
4-cxo-cinnamoyloxy-11-anti-dimethylamino-benzo(b)bicyclo~3.3.1]nonene,HCl.
- 22 -
- 1~779S4
4-exo-decanoyloxy-ll-anti-dimethylamino-benæo(b)bicyclo[3.301]nonene.HCl.
4-exo-~lcetox~-8-bromo-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl.
4-endo--benzoyloxy-8-chloro-ll-syn-dimethylamino-benzo(b)bicyclo[3.301]nonene.
HCl.
4-exo-~2,2-dimethylpropionyloxy)-8-chloro-11-anti-dimethylamino-benzo(b)
bicyclo[30301]nonene.HCl.
4-endo-benzoyloxy-8-chloro~ anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.
HCl.
4-exo-acetoxy-8-chloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3~1]nonene.HCl.
4-exo-benzoyloxy-8-chloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.
HCl.
EXAMPLE_XV
4-exo-acetoxy-ll-anti-acetamido-benzo(b)bicyclo[3-~3-~l~noneneo
4-exo-hydroxy-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene (20 g) is
suspended in acetic anhydride (40 ml) and the mixture stirred at room
temperature for 1 hour, and then poured into water. The solid is collected
and dried to give 4-exo-acetoxy-ll-anti-acetamido-benzo(b)bicyclo[303,1]
nonene (12.6 g), m.p. 213-214.
In the same manner is prepared with (phenyl)propionylchloride;
4-exo-phenylpropionyloxy-11-anti-phenylpropionylamido-benzo(b)bicyclo[3.3.1]
nonene,
4-exo-propionyloxy-11-anti-propionylamido-benzo(b)bicyclo[3~3.1]nonene.
A stirred suspension of 4-exo-benzoyloxy-8-chloro-11-anti-amino-
benzo(b)bicyclo~3,3.1]nonene in acetic anhydride r0sults in the same manner
as described above in 4-exo-benzoyloxy-8-chloro-11-anti-acetamido-benzo~b)
bicyclo[3.3.1]nonene, identical with the product obtained in Example Xl.
A stirred mixture of 4-exo-benzoyloxy-8-chloro-11-anti-
. . ~ .,
~ ) ~i -23-
.... , ~
: .
1C~77954
amino-benzo(b)bicyclo[3.3.1]nonene and benzoyl-chloride in toluene results
in: 4--exo-benzoyloxy-8-chloro-11-anti-benzoylamldo-benzo~b)bicyclo[3.3.1]
nonene.
EXAMPLE XVI
4-exo-hydroxy-11-anti-ethylamino-benzoCb)bicyclo[3.3.1]nonene.HCl.
-
To a suspension of LiAlH4 (3.3 g) in dry tetrahydrofuran is addeda hot suspension of 4-exo-acetoxy-11-anti-acetamido-benzo(b)bicyclo[3.3.1]
nonene (12.5 g) in a mixture of tetrahydrofuran and dioxan (300 ml) and the
mixture refluxed for 2 hours. The excess lithium aluminium hydride is
destroyed by the addition of water, the mixture filtered and the filtrate
evaporated to dryness. The residue is dissolved in ether, treated with a
saturated solution of hydrogen chloride in ether and the solid formed is
recrystallised from methane-ether to give 4-exo-hydroxy-11-anti-ethylamino-
benzo(b)bicyclo[3.3.1]nonene hydrochloride (12 g), m.p. > 265.
In the same manner is prepared:
4-exo-hydroxy-11-anti-phenylpropylamino-benzo(b)bicyclo[3.3.1]nonene.HCl,
4-exo-hydroxy-11-anti-propylamino-benzo(b)bicyclo[3.3.1]nonene,
4-exo-hydroxy-8-chloro-11-anti-ethylamino-benzo(b)bicyclo[3.3.1]nonene,
4-exo-hydroxy-8-chloro-11-anti-cyclopropyllmethylamino-benzo(b)bicyclo
[3.3.1]nonene,
4-exo-hydroxy-8-chloro-11-anti-p-hydroxyphenethylamino-benzo(b)bicyclo
[3.3.1]nonene.
EXAMPLE XVII
4-exo-Hydroxy-ll-anti-N-methyl-N-(3-methyl-but-2-enyl)-amino-benzo(b)
bicyclo[3.3.1]nonene hydrochloride.
To a stirred suspension of 4-exo-hydroxy-11-anti-methylamino-
benzo(b)bicyclo[3.3.1]nonene (5.5 g) and potassium bicarbonate (5.0 g)
in dimethyl formamide (10 ml) and methylene chloride (1 ml) is added
_ 24 -
1~77~54
dropwise a solution of l-bromo-3-methyl-but-2-ene (5.5 ml) in dimethyl
formamide (10 ml) whilst maintaining the mixture at room temperature.
The reaction mixture is stirred for a further 15 minutes and then poured
into water. The product is extracted with methylene dichloride. The
extract is washed with water, dried and evaporated to give an oil, which is
chromatographed on alumina. Elution with benzene gives an oil (5 g) which
is dissolved in ether and treated with a saturated solution of hydrogen
chloride in ether. The solid formed is recrystallised from methanol-ether
to give 4-exo-hydroxy-11-anti-N-methyl-N-(3-methyl-but-2-enyl)-amino-benzo(b)
bicyclo[3.3.1]nonene hydrochloride (3.1 g), m.p. 258-259.
EXAMPLE XVIII
In an analogous manner as described in Example I various benzo(b)
bicyclo[3.3.1]nonene derivatives are prepared by reacting 4-exo-benzoyloxy-
8-chloro-benzo(b)bicyclo[3.3.1]nonen-11-one with the desired amine of formula
III in the presence of formic acid or with the amine salt of formic acid,
whether or not dissolved in a suitable inert solvent. In this manner are
prepared:
4-exo-benzoyl-8-chloro~ anti-morpholino-benzo(b)bicyclo[3.3.1]nonene,
4-exo-benzoyl-8-chloro-11-anti-piperidino-benzo(b)bicyclo[3.3.1]nonene,
4-exo-benzoyl-8-chloro-11-anti-pyrrolidino-benzo(b)bicyclo[3.3.1]nonene.
EXAMPLE XIX
Various 4-hydroxy-benzo(b)bicyclo[3.3.1]nonene-11-oxime derivatives
are reduced with sodium in isopropanol to give the corresponding primary
amines I. The oximes are obtained by reaction o~ 4-(endo or exo)-benzoyloxy-
benzo(b)bicyclo[3.3.1]nonen-11-one derivatives with hydroxylamine.HCl in
sodium hydroxide and ethanol. The following compounds are prepared:
4-exo-hydroxy-8-methoxy-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene.HCl,
m.p. 256-258~C,
- 25 -
.; .
: -
1~77~54
4-exo-hydroxy-8,9-dichloro-11-anti-amino-benzo(b~bicyclo~3.3.1]nonene.HCl,
m.p. 286-300C,
4-exo-hydroxy-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene.HCl, sublimation
265C.
EXAMPLE XX
In the same manner as described in Example I the following com-
pounds are prepared by refluxing the appropriate starting ketone in a
mixture of formic acid and formamide or dimethylformamide respectively:
4-exo-p.nitrobenzoyloxy-9-chloro-11-anti-formamido-benzo(b)bicyclo[3.3.1]
nonene.HCl, m.p. 269-272C;
4-exo-p.nitrobenzoyloxy-8-nitro-9-chloro-ll-anti-formamido-benzo(b)bicyclo
[3.3.1]nonene.HCl, m.p. 276-279 (dec.);
4-exo-p.nitrobenzoyloxy-9-chloro-10-nitro-11-anti-formamido-benzo(b)bicyclo
[3.3.1]nonene.HCl, m.p. 253-262C (dec.);
4-endo-p.nitrobenzoyloxy-8-nitro-9-chloro-11-anti-formamido-benzo(b)bicyclo
[3.3.1]nonene.HCl, m.p. 229-231C;
4-exo-hydroxy-8-chloro-9-nitro-11-anti-formamido-benzo(b)bicyclo[3.3.1]nonene.
HCl, m.p. 248C;
4-exo-methoxy-8-chloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene,
(oil);
4-exo-hydroxy-8-t.butyl-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene
(oil);
4-exo-decanoyloxy-8-chloro-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1
nonene, HCl.
- 26 -
