Note: Descriptions are shown in the official language in which they were submitted.
1051877
The present invention relates to novel biologically active
amino-substituted tetracyclic compounds and to processes for the preparation
thereof.
The invention provides compounds of the general formula I:
I
~ R5`
(CH2) n~N \
as well as the pharmaceutically acceptable acid addition and quaternary
ammonium salts thereof, in which X represents oxygen, sulphur, the group
= NR7 or the group -CH2-, ring A is either unsubstituted or substituted
in the 6- or 7-position by a halogen having an atomic number not greater
than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4
carbon atoms or a hydroxy group, ring B is either unsubstituted or substituted
in either or both of the ll-and 12-positions by a halogen having an atomic
number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl
group of 1 to 4 carbon atoms, a hydroxy group or a trifluoromethyl group,
R5 and R6 are the same or different and represent hydrogen atoms or alkyl
groups of 1 to 4 carbon atoms which are either unsubstituted or substituted
by a phenyl group, or the group NR5R6 together represents a morpholino,
piperidino or W rrolidino group, R7 represents hydrogen or methyl, n is zero,
one or two, and the dotted line in the nucleus signifies an extra bond which
is optional when n is zero, possess valuable C.N.S. activities. The
toxicity of these compounds is exceedingly lowO
The compounds according to the invention may be prepared in a
manner commonly used for analogous compounds. Thus, according to the
invention, the compounds of fo Dula I and their salt, as defined above, are
prepared by a process which comprises either:
D -1-
105~877
a) condensing a compound of the general formula IV:
IV
~ 2)n
in which n and X are as previously defined and Y is a leaving group~ with
ammonia or an amine of the general formula V:
"~R5-~ V
R6~
or an acid addition salt thereof, wherein R5 and R6 are as previously defined;
or
b) reducing a compound of the general formula VI:
~ ~ VI
in which R represents - (CH2)p -CN or -~CH2)pN3 wherein p represents zero
or one and X is as previously defined; or
c) for preparing compounds of general formula I in which n is zero and
the dotted line in the nucleus signifies an extra bond, reacting a compound
of the general formula V as defined above with a compound of the general
formula II:
II
la-
105~77
in which X is as previously defined in the presence of a reducing agent; or
d) reducing a compound of the general formula IX:
IX
(CH2)n~N 5 ~
R6
in which R5, R6, X and n are as previously defined, or
e) for preparing compounds of general formula I, in which n is zero
and the dotted line in the nucleus signifies an extra bond, reducing a
compound of the general formula VII:
VII
~OH
in which X is as herein before defined, by reaction with a metal hydride
or by catalytic hydrogenation; or
f) for preparing compounds of general formula I, in which n is zero
and the dotted line in the nucleus does not signify an extra bond reducing a
compound of general formula VII as defined above by reaction with sodium or
sodium amalgam; or
g) for preparing compounds of general formula I in which n ~-1,
reducing a compound of general formula VIII:
,~ ~ VIII
~C~12)p
,-R
R ~J
-lb-
/
~OS~877
in which R5, R6, X and p are as previously defined; and wherein steps (a) to
(g) may be followed by the additional step of alkylating or phenylalkylating
a compound of formula I obtained in which one or both of R5 and R6 is hydrogen
to obtain the corresponding compound of formula I in which one or both of R5
and R6 are alkyl or phenylalkyl groups; and wherein a base of formula I may
be connected into a corresponding pharmaceutically acid addition or quaternary
a~rcniu~ salt.
", ~''
,/
,,, . , . . . , , . . . , , , . ~
-lc--
~'
J
1051877
The compounds II are, as far as known, novel compounds. They can be prepared
in various manners. The most simple method to prepare the compound II is the
condensation of vinylmethylketone (CH3-C-CH=CH2) with a compound of the
general formula III:
~ III
in which A, B and X have the meanings mentioned above. This condensation re-
action in preparing the starting material II is performed in a suitable sol-
vent, preferably in the presence of a base, such as sodium hydroxide, potas-
sium hydroxide, sodium ethoxide or sodium hydride. An intermediate product
formed in this condensation reaction, namely a compound of formula III with a
y-keto-butyl moiety at position 6, can, if desired, be isolated though it is
not necessary to do so.
Starting from a compound with formula II the end products
according to formula I can be prepared in various manners. All these routes
are known per se and are standard procedures commonly used for the preparation
of si=ilar compounds. ~
r~
,, ~
~51877
In the compounds of general formula IV, Y represents a suit-
able leaving group, Y is e.g. halogen or an etherified or esterified hydroxyl
group. Leaving groups are well defined groups, described in various chemical
handbooks. Thus suitable leaving groups for this condensation reaction are
for example a tosyloxy group, a mesyloxy group, a p-bromophenyl-sulphonyloxy
group, a chlorine, bromine or iodine atom.
The compound IV required for this condensation reaction may
be prepared from the starting material II described before by reducing the
keto group to a hydroxyl group, preferably with metal hydrides such as LiAlH4,
diboran or in particular NaBH4, followed by converting this hydroxyl group
into the desired leaving group in a conventional manner, for instance by
tosylation,~
/'
D
1~518~7
mesylation, reaction with SOCl , PC15, PBr3, etc.
Extension of the alkyl chain (from n=O to n=l or 2) can be
performed in the usual way, for instance by treating a compound IV, in
¦ which n=O, with a cyanide such as potassium- or sodiumcyanide. The cyano-
group in the compound thus obtained can then be hydrolysed to the corres-
ponding carboxyl group. A further extension of the alkyl chain can be
obtained by reducing the carboxyl compound to afford the hydroxy-methyl
compound. The hydroxy-methyl compound thus obtained is converted into a
compound in which the hydroxyl group is replaced by a leaving group, and
repeating the above-mAntioned cyAnide r.action.
lOS1877
The reduction of compounds of formula VI is performed in
the usual way for this kind of compounds. The cyanide group is preferably
reduced by means of metalhydrides, especially lithium-aluminium-hydride~
the azide group by a metalhydride such as LiAlH4 or NaBH4 or by hydrogenation
in the presence of a metal catalyst such as palladium, Raney nickel, etc.
The starting materials with formula VI required in this
method can, for example, be prepared by treating a compound of formula IY
with sodium cyanide or sodium azide.
Suitable reducing agents for use in the reaction of the
starting material II with the amine according to formula V in the presence
of a reducing agent, are metalhydrides, e.g. NaBH4, LiAlH4, NaCNBH3, etc.
but preferably formic acid (Leuckart reaction) or hydrogen in the presence
of a suitable catalyst, such as palladium, palladium on charcoal, Raney
nickel, etc.
This reductive amination is well-known in organic chemistry
and described in any chemical handbook.~
/
/
': /
D
1051877
The reduction of a compound VII may be performed by hydro-
genation preferably in the presence of a usual metallic hydrogenation
catalyst, or with metalhydrides such as LiAlH4.
The compound VII is prepared direct from the corresponding
keto co~pound II by treating the latter with hydroxylamine in the usual way,
or indirect from the keto compound II by reacting it with isoamylnitrite/
potassium-t.butoxide yielding the 2-keto-3-oxime compound, followed by a
Wolff-Kishner reduction of the keto group.
The reduction of a compound VIII is carried out in a conven-
tional manner for the reduction of amides, for example with metalhydrides,
especially LiAlH4.
The starting compounds YIII for this reduction can, forexample, be prepared by hydrolysis of the cyano-compound of the general
formula VI, yielding the corresponding carboxyl compound, which compound
is converted into the corresponding amide in the usual way, for example by
_ - 7
~ _ ____ __ _ _ _
--6--
1051877
halogenating the carboxyl group affording the acid halide, followed by re-
acting the acid halide with an amine of the formula V. The primary amide
of formula VIII may, of course, be prepared directly by partial hydrolysis
of the cyano-compound VI.
Finally, the reduction of a compound IX is carried out in a
conventional manner, for example with metalhydrides, such as LiAlH4, etc.
or by hydrogenation in the presence of a catalyst such as palladium, pal-
ladium on charcoal, Raney nickel, etc.
The starting compounds IX may be prepared in ~arious manners.
For example, a compound IX with n-O (enamine) may be prepared by treating
the ketone II with an amine of formula V, preferably in the presence of a
Lewis acid, such as AlC13, SnC14, etc.
A compound IX with n=l may be prepared by treating the
ketone II with HCN, eliminating the hydroxyl group formed to obtain a
double bond and con~erting the cyano ~ ~
D~
~05~877
group in a conventional manner into an aminomethyl group. Another method
consists of the rcaction of the ketone II with the reagent (CH3)2S(~ 0)=CH2,
whereupon the compound thus obtained is treated with the amine V followed
by eliminating the hydroxyl group formed to obtain a double bond.
A compound IX with n = 2 may be obtained by a Wittig reaction,
a Wittig-Horner reaction, a Reformatski reaction or a reaction with
acetonitrile carried out on the starting ketone II. Reagents necessary
in these reactions are well-known and described in any chemical handbook,
for example: Ph3P=CH-B' (Wittig), (EtO)2-P(-~ O)-cH2-coR~ in NaH and a
suitable solvent (Wittig-Horner), BrZn-CH2-COR' (Reforma~ski) and CH3CN
in the presence of sodiumalkoxide, whereby Ph stands for an aryl group,
in particular a phenyl group, B' represents a -CH2-N ~ 5 ~ moiety or a group
R6~
that can easily be converted into this aminomethyl moiety, such as a
carboxyl group, an esterified carboxyl group, an amide group, a cyano group
or a hydroxyl group, and R' stands for an esterified hydroxyl group. An
additional reaction may then be necessary to convert these moieties into a
carboxyl group.
The Reformatski reaction requires an additional step to obtain
the al(2) double bond by elminating the hydroxy group formed, whereas in
all methods in which the amino-moiety is not present already in the reagent
used, an additional reaction has to be carrird out in order to convert the
moiety present (carboxyl, hydroxy, cyano, amide, etc.) into the desired
amino-moiety.
Most reactions described preparing the starting material IX
involve-the reduction of a cyano group or- ,~
,
,,
1051877
an amide group. It is, of course, possible to reduce these moieties
simultaneously with the al(2) double bond present in the molecule.
In all afore-mentioned methods, in which a reduction has been
carried out in the last step of the synthesis or in one of the previous
steps, the conjugated double bond between the phenyl nuclei is not reduced
under the usual reaction conditions.
By carrying out the reduction in question und~r strong reductive
conditions, e.g. by increasing the reaction temperature and reaction time,
by increasing the quantity of the reducing agent and/or by performing the
reduction under high pressure, it is possible to isolate also the compounds I
with a saturated C-C bond instead of the C=C bond, in particular where a
catalytic hydrogenation with PtO2 in acetic acid has been used for the
reduction.
A more preferred synthesis for the preparation of these
"saturated" compounds I consists of the reduction of the compound VII:
VII
N-OH
in which A, B and X have the aforesaid meanings, with sodium or sodlumamalgam
in a suitable liquid, such as sodium in isopropanol, or by a hydrogenation
in the presence of platinumoxide (Adams - ~
D
1051877
catalyst) under the usual conditions, especially in acetic acid. In this
reduction the ~4a(13b) double bond as well as the oxime moiety are reduced
simultaneously.
The best method for the preparation of the compounds I, in which
the 4a~13b) bond is saturated, consists of a reduction of the ~4a(13b)
double bond of the ketone II.
A catalytic hydrogenation of the ketone II with platinumoxide in
a suitable liquid, preferably acetic acid, yields the corresponding 4a(13b)-
saturated alcohol X quantitatively:
~ X
OH
in which A, B and X have the meanings afore-defined. This alcohol X may
be oxidized to the 4a(13b)-saturated ketone of the general formula XI:
~ XI
o
in which A, B and X have the meanings afore-defined. This oxidation may
be carried out in a conventional manner, for example with manganesedioxide
or chromic acid-pyridine complex. A very useful oxidation is the biphasic
one in which a benzenic solution of the alcohol X is shaken with a solution
of CrO3 in acetic acid/water mixture. ~ C_
.. ... , _ . .. . . ..... ..
_10-
1051877
All additional reactions described before starting from the
"unsatuTated" ketone II or the corresponding alcohol, yielding the
"unsaturated" compounds I can also be applied to the ketone XI or the
corresponding alcohol X to obtain the 4a(13b)-saturated compounds I. In
other words the ketone XI or the alcohol X can be converted into the 4a(13b~-
saturated analogues of the compounds IV, VI, VII, VIII or IX followed by
conversion of these compounds into the 4a(13b)-saturated compounds I in
the manner described. The ketone XI can further be subjected to the
reductive amination as described previously.
. .,
lO ' A specific series of biologically active intermediates used in
the present methods for the preparation of the compounds I are compounds of
the general formula XII:
~ ~ XII
~>
(CH2)n-1 COOH
as well as salts and esters thereof, in which A, B, X and n have the
aforesaid meaning. These intermediates exert potent anti-inflammatory
activity. They can be administered orally, parenterally or locally in a
daily dose of from 0.1 mg to 10 mg per kg/body weight.
These compounds XII can be prepared in various manners,
indicated already in this specification. In this connection there is
referred to the hydrolysis of a cyano group and to methods such as the
hi Wl g ~n r an ~ o na
~ ... . , . . . . .. ... _ . ,. ... _ . ......... . . . .. ... . .. .
-1 1--
1051~77
reactions mentioned previously~ In the latter methods the
double bond (~1,2) has to be reduced additionally by means
of a catalytic hydrogenation.
Compounds XII with n = 0 can further be prepared by
treating a compound of formula IV, in which Y stands for
halogen, in particular lodine, with magnesium, after which
the magnesium halide thus obtained ~Y - .~gHal) is converted
into the corresponding carboxyl-compound by treating with
CO2 ~
Esters of the compound XII are derived from alipha~-ic,
cycloaliphatic, aromatic or araliphatic alcohols w1th 1-18
carbon atoms, which may be substituted by hydroxy or halogen
groups, especially lower aliphatic alcohols with 1~6 carbon
ato~s, or phenylaliphatic alcohols with 7-10 C-atoms, such
as methanol, ethanol, isopropanol, butanol, hexanol, phen-
ethylalcohol~ benzylalcohol, phenylpropylalcohol, p-chloro-
benzylalcohol~ p-hydroxyphenethylalcohol~ etc.
The compounds according to the invention contain an
asymmetric carbon at position 2 of the tetracyclic molecule.
Besides the racemate optical antipodes are thus possible
which also belong to the compounds according to the invention.
These optical isomers are prepared from the corresponding
racemate by a resolution in the usual way. By resolving a
starting product or an intermediate product in the syn-
thesis, the optical isomers can also be obtained in a
direct way.
The pharmaceutically acceptable salts of the compounds
I according to the invention are acid addition salts and
- 12 -
1051877
quaternary ammonium compounds.
The novel compounds of the formula I may be isolated from
the reaction mixture ln the form of a pharmaceutically accept-
able acid additlon salt, dependent upon the conditions in
S which the reaction is carried out. The acid addition salts
may also be obtained by treating the free base with a
pharmaceutically acceptable organic or ~norganic acid. Aclds
that can be used in this connection are; hydrochloric acid,
hydrobromic acid or hydroiodic acid, phosphoric acid, acetic
acid, propionic acid, glycollic acid, maleic acid, malonic
acid, succinic acid, tartaric acid, citric acid, ascorbic
acid, salicylic acid or benzoic acid.
The quaternary ammonium compounds and in particular the
lower (1-4 C) alkyl quaternary ammonium compounds are ob-
tained by reacting the compounds of the general formula Iwith an alkyl halide, for example methyl iodide or methyl
bromide.
It is possible as a matter of cours~ to introduce or to
modify the substituents at one or both phenyl nucleii even
after the condensation reactions described before. Thus a
hydroxyl group can be converted into an alkoxy group, an
amino group into a hydroxy- or halogen group, a methoxy
group into a hydroxy group etc.
The unsubstituted or monosubstituted amines of the
general formula I (R5 andJor R6 ~ H) may be alkylated
in the usual way, for example by reaction with an alkyl-
or ar~lkylhalide. More common for this purpose is, how-
ever, the acylation of the nitrogen atom in question with,
for example, an acid chloride or anhydride followed by a
~51877
reduction of the carbonyl group of the N-acyl derivative
thus obtained. For the introduction of methyl groups at
the nitrogen atom the procedure accordinq to Eschweiler-
Clarke (heating with a mixture of formaldehyd and formic
acid) or the reaction with formaldehyde and sodlumcyano-
borohydride in a suitable solvent~ such as acetonitril,
is preferred.
With an alkyl group with 1-6 carbon atoms is meant a
branched or un~ranched alkyl group such as methyl, ethyl,
propyl, isopropyl~ butyl, isobutyl, tert.butyl, n.pentyl5
isopentyl and hexyl.
The alkyl group in the alkoxy and alkylthio moieties
has the same meaning.
An aralkyl group mentioned in the definition of R5 and
R6 is preferably a phenylalkyl group, in which the alkyl
group contains 1-4 carbon atoms, such as benzyl, phenyl-
ethyl, phenylpropyl, phenylisopropyl, phenylbutyl and
phenylisobutyl.
The heterocyclic 5- or 6-membered ring (definition of
R5 and R6) may either be saturated or unsaturated, such
as a pyrrolino group, a pyrrolidino group, a piperidino
group, an oxazolidino group, a morpholino group, a pi-
perazino group, etc.
Amines according to the general formula V~ that may
be used in the various condensation reactions to obtain
the compounds of the invention, are, ~or example ammonia~
methylamine~ dimethylamine, diethylamine, isopropylamine,
dibutylamine, t.butylamine, benzylamine, phenylethylamine,
phenylpropylamine, 2-phenyl-1-methyl-ethy$amine, pyrroline,
- 14 -
1051~i7
pyrrolidine, piperidine, oxazolidine, morpholine, piperazine,
etc.
As already pointed out previously the compounds of the
invention I exert a valuable central nervous system activity.
This C.N.S. activity can be concluded from the results of
various pharmacological experiments, such as the reserpine
antagonism test, reserpine reversal test, aggression iso-
lated mice test, ambulation test, rotarod test, grip strength
test, muricidal inhibition test, etc.
The surprising high activity of the compounds I in anta-
gonizing hypothermia induced by reserpine (reserpine anta-
gonism test) give strong indications that the present com-
pounds can be used as antidepressants.
The compounds I may be administered both orally and
parenterally, preferably in a daily dose of from 0.1 to 10
mg per kg bodyweight.
Mixed with suitable auxiliaries the present compounds
can be compressed into solid dosage unlts such as pills,
tablets or coated tablets, or they can be processed into
capsules. With the aid of suitable liq~ids the compounds
can be applied as in~ection preparations in the form of
solutions, emulsions or suspensions.
Preferably compounds I and, in particular,compounds
I A are used in which X stands for a methylene moiety
(-CH2-) or a /N-alkyl moiety, in particular a ~N~CH3
moiety. Especially the latter type of compounds (X =
,N-alkyl) excels in a very potent antidepressant activity.
Furthermore the compounds I, in which n iS 0 or 1 are
to be preferred over the compounds I, having a longer side
chain (n ~ 2).
- 15 -
1051877
In the Examples the following nomenclature and numbering
has been used:
\ / ,0
5 ~ ~ 1,2,3,4-tetrahydro-9H-tribenzo
~12 ( b,d,f)-cycloheptatriene
8 g lo
10 ~ ~ x ~ X = 0 or S
1,2,3,4-tetrahydro-tribenzo(b,d,f)-
5 ~4 ~ ~3 oxepine or -thiepine
W
q ,0
~ ~ ~,2 1~2~3~4-tetrahydro-9H-tribenzo
~ ~ (b,d,f)-azepine
By way of example the preparation of various starting
products are disclosed. The preparation of analogous starting
products proceeds in exactly the same way.
Preparation startinq materials
25 1. 2-keto-1~2~3~4-tetrahvdro-tribenzo(b~d~f)-oxePine
To a solution of 42 g of the compound 10-keto-10,11-dihydro-
dibenzo(b,f)-oxepine in 200 ml of dry ethanol a solution of
sodiumethoxide (7 g of sodium ln 500 ml of ethanol) is added
dropwise. After stirring the mixture for 30 minutes 16.2 ml
of methylvinylketon in S0 ml of ethanol are added, where-
- 16 -
~051877
upon the solut~on is refluxed for one hour. The solution
i~ cooled then and poured into 2 N HC1. After extracting
into ether, washing the ether layer with water (till
neutral) and drying the etherial phase, the solvent is
S evaporated.
The residue, a redcoloured oil, is chromatographed after
that over an alumina column and used ~or further con-
version immediately. Yield: 37% oil.
In the same manner are prepared:
2-keto~ methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
meltin~ point 146-147C.
2-keto-11,12-dimethyl-i,2,3,4-tetrahydro-tribenzo(b,d,f)-
oxepine; (oil).
2-keto-12-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point 107-108C.
2-keto-11-trifluoromethyl-1~2,3,4-tetrahydro-tribenzo(b,d,f)-
oxepine; (oil).
2-keto-6-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point 128-129C.
2-keto-6-methyl-1,2,3,4-tetrahydro-tribenzo(bgd,f)-oxepine;
(oil).
2-keto-1,2~3~4-tetrahydro-tribenzo(b,d,f)-thiepine; (oil).
2-keto-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cyclohepta-
triene; melting paint 132-133C.
2-keto-12-hydroxy-1,2,3,4-tetrahydro-9H-tribenzotb,d,f)-
cycloheptatriene; (oil).
2-keto-12-methoxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-
cycloheptatriene; (oil).
2-keto-11-methyl-12-methoxy-1,2~3,4-tetrahydro-9H-tribenzo
(b,d,f)-cycloheptatriene; (oil).
- 17 -
- 10~1~377
2-keto-12-methyl-1~2,3,4-tetrahydro-9H-tribenzo(b~d,f)-
cycloheptatriene; melting point 158-163C.
2-keto-12-trifluoromethyl-1,2~3,4-tetrahydro-9H-tribenzo
(b,d,f)-cycloheptatriene; (oil).
2-keto-7-chloro-1~2,3,4-tetrahydro-9H-tribenzo(b,d~f)-
cycloheptatriene; (oil).
2-keto-1,2~3,4-tetrahydro-9H-tribenzo~b,d,f)-azepine; ~oil).
2-keto-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d~f)-
azepine; loil).
2-keto-7-methoxy-9-methyl-1,2,3,4-tetrahydro-gH-triben2O
(b,d,f)-azepine; (oil).
¦ 2. ;2-hvdroxY-1,2~3,4-tetrahYdro-tribenzo(b,d,f)-oxepine
~ J 6.2 g of 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine
are added to a suspension of 3.7 g of lithiumaluminiumhy-
dride in 300 ml of dry ether. After refluxing for 2 hours
14.8 ml of water are added carefully. The suspension ob-
tained is filtered off and after that the filtrate is
dried and evaporated to dryness.
3. 2-hvdroxv-1~2~3,~4a,13b-hexahydro-tribenzo(b,d.f)-oxepine
1.0 g of 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine
is added to a suspension of 10 mg PtO2 (Adams catalyst) in
50 ml glacial acetic acid. The mixture is put in a hydro-
genation apparatus under hydrogen atmosphere and shakenfor 3 hours. After that time the theoretical quantity of
hydrogen has been absorbed. The mixture is then filtered
to remove the catalyst, whereupon the filtrate is evapo-
rated in vacuo, yielding a light yellow oil.
- 18 -
10518'-~'7
4. 2-mesyloxy-1,2,3,4-tetrah~dro-tribenzo(b,d,f)-oxepine
6.2 g of 2-hydroxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-
oxepine are added to a mixture of 16.8 ml of pyridine
and methane sulphonylchloride, after which the mixture
is stirred for 2 hours at 0C and then another 2 hours
at room temperature. After that ~he mixture is poured
out into water and then extracted with ether. The ether
layers are dried and evaporated to dryness.
5. 2-azido-1 ? 2,3.4-tetrahydro-tribenzo(b,d,f)-oxepine
The mesylate obta~ned in 3 in brought into a mixture of
25 ml of dimethylformamide and 4.2 ml of water, to which
1.52 g of activated sodium azide is added. The mixture
is refluxed for S hours. After cooling the mixture is
poured out into water and extracted with ether. After
that the ether layers are washed, dried and evaporated
to dryness.
! 6. 2-cvano-1.2.3~4-tetrahYdro-trlbenzo(b.d,f)-oxePine
2~ ~ 2.62 g of the 2-hydroxy compound obtained in 2 is-dis-
solved in 50 ml of benzene whereupon 5 g of phosphorus
triiodide is added. The mixture is refluxed for 2 hours.
After cooling this mixture ice-water is cautiously added.
The organic layer is separated, washed with water and
dried. The solvent (benzene) is then evaporated yielding
3.6 g of the oily 2-iodo-compound. This residue is imme-
diately dissolved in 300 ml dimethylformamide, after which
4 g sodiumcyanlde is added. The mixture obtalned is heated
at 90C for one hour stirring all the time. The reaction-
mixture is then poured into 600 ml water and extracted
- 19 -
1051877
with ether. The crude nitrile is obtained after evaporat~on
of the ether and immediately used for further reactions.
7. 2-cyanomethylidene-1,2,3~4-tetrahydro-tribenzo(b~d,f)-
oxepine
1 g of 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine
is mixed with 1 ml of benzene, 15 ml of acetonitril and
0.5 g of molecular sieve (4 ~). 50 m~ of sodium-ethoxide
are added and the mixture is heated for 3 hours (90-100C).
After cooling the mixture the molRcular sieve is filtered
off and the filtrate evaporated.
Example I
2-amino-1.2,3,4-tetrahYdro-trlbenzo(b,d,f)-oxepine
3.7 g of 2-azido-1,2,3,4-tetrahydro-tribenzo~b,d,f~-oxepine
are added to a suspension of 3 g of lithiumaluminiumhydride in
100 ml of dry ether. The mixture is refluxed for one hour.
After the mixture has been cooled down, 12 ml of water are
added carefully after which the mixture is stirred for some
time~ The suspension is filtered and after that the filtrate
ls dried and evaporated to dryness. The residue is converted
with maleic acid into the maleate. Melting point of the
maleate: 198-202C. Yield 85X.
Example II
In the way indicated in example I are prepared:
2-amino-9-methyl-1~2~3~4-tetrahydro-9H-tribenzo(b,d,f)-azepine,
(oil).
2-amino-7-chloro-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-
azepine, (oil).
2-amino-1,2,3,4-tetrahydro-9H-tribenzo(b~d,f)-cycloheptatrien~;
melting point as maleate: ]85-188C~
- 20 -
1~51~77
2-amino-12-methoxy-1~2~3,4-tetrahydro-9X-tribenzo(b~d,f)-
cycloheptatr~ene; melting point as maleate: 165C (dec.).
2-amino-12-methyl-1,2~3,4-tetrahydro-9H-tribenzo(b,d,f)-
cycloheptatriene; melting point as maleate: 196-201C.
2-amino-7-chloro-1~2~3,4-tetrahydro-9H-tribenzo(b,d,f)-cyclo-
heptatriene, (oil).
2-amino-11-trifluoromethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-
oxepine, (oil).
2-amino-11-methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point as maleate: 190-192C.
2-amino-12-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point as maleate: 194-196C.
2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine;
melting point as maleate: 178-180C.
2-amino-12-trifluoromethyl-1,2,3,4-tetrahydro-9H-tribenzo
(b,d,f)-cycloheptatriene, (oil).
2-amino-12-hydroxy-1~2,3,4-tetrahydro-9H-tribenzo(b~d,f)-
cycloheptatriene, (oil).
,.
Example III
2-dimethylamino-1,2~3.4-tetrahYdro-9H-tribenzo(b~d,f)-cyclo-
heptatriene
In a 500 ml Parr apparatus a mixture of 20 g 2-keto-
1,2,3,4-tetrahydro-tribenzo(b,d,f)-cycloheptatriene in 300
ml of absolute ethanol and a solution of 6 g of dlmethyl-
amine in 20 ml of ethanol to which 3.9 g of palladium 10%
on charcoal are added, is hydrogenated by means of hydrogen
under a pressure of 3 kg/cm2.
The mixture is then filtered and the filtrate washed,
dried and evaporated to dryness. The residue is an oily
~051877
substance. The oil ls crystallized by means of maleic acid.
Melting point after recrystallization from ether-ethanol
145-150C and 169-171C (double melting point).
Treatment of the free base with methyliodide resulted
in the iodo methylate~
Example IV
2-dimethYlamino-6-chloro-ll2~3~4-tetrahydro-triben2o(b.d~f)
oxePine
To a mixture of 10 ml of dimethylamine and 3.1 ml of 98%
formic acid at -10C a solution of ll.S g of 2-keto-6-chloro-
1~2~3,4-tetrahydro-tribenzo(b,d,f)-oxepine in 30 ml of dime-
thylformamide are added dropwise. The mixture is refluxed for
10 hours. After cooling, the mixture is poured into water and
extracted into ether. The ether layer is then washed with 300
ml of 2 N HCl. The acidic water layer is made alkaline with 2
N NaOH, after which the alkaline aqueous solution is extracted
with ether once more. The ether layers are collected, dried
and then evaporated. The oil obtained crystallizes as maleate:
melting point 171C.
Example V
2-dimethvlamino-12-methoxv-1,2,3l4-tetrah~dro-9H-tribenzo
(b~d~f)-cYcloheptatriene
500 mg of 2-keto-12-methoxy-1,2,3,4-tetrahydro-9H-tri-
benzo(b,d,f)-cycloheptatriene in 2.7 ml of methanol is
treated with 150 mg of sodiumborohydride and 0.14 ml of
/~et~y~ e
methanolic IICl solution (5 N). After mixing for 10 hours
at an elevated temperature, the reaction mixture is
filtered and the filtrate extracted with ether. The ether
- 22 -
- ~)51877
layer is washed, dried and evaporated. The oil obtained is
then chromatographed over an alumina column. Melting point
as HCl salt: 210C. Yield 30%.
Example VI
In the way indicated in example III are prepared:
2-dimethylamino-7-methoxy-9-methyl-1,2 9 3 ~ 4-tetrahydro-9H-
tribenzo(b,d,f)-azepine, (oil).
2-amino-1,2,3 f 4-tetrahydro-9H-tribenzo(b,d,f)-cyclohepta-
triene; melting point as maleate: 183-185C.
2-methylamino-1,2,3,4-tetrahydro-9H-tribPnzo(b,d,f)-cyclo-
heptatriene; melting point as maleate: 162-165C.
2-dimethylamino-12-methoxy-1,2,3,4-tetrahydro-9H-tribenzo
(b,d,f)-cycloheptatriene; melting point HCl salt: 210C
(dec.).
2-dimethylamino-12-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-
oxepine; melting point maleate: 195-196C.
2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine;
melting point HCl salt: 250-255 C (dec.).
2-morpholino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine,
(oil).
2-dimethylamino-9-methyl-1,2~3~4-tetrahydro-9H-tribenzo(b,d,f)-
azepine, (oil); maleate salt 212-218C.
2-methylamino-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo~b,d,f)-
azepine, (oil).
2-piperidino-9-methyl-1,2~3,4-tetrahydro-9H-tribenzo(b,d,f)-
azepine, (oil).
2-benzylamino-9-methyl-1,2~3,4-tetrahydro-9H-tribenzo(b~d~f)-
azepine, (oil).
2-benzylamino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cyclohep-
tatriene, (oll).
- 23 -
1~51877
2-phenethylamino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cyclo-
heptatriene, (oil). -~
~ I ~ 0l ne ~
2-amino-1,2,3~4-tetrahydro-tribenzo(b,d,f)l ~ ,~(oil);
melting point maleate: 178C~
2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)_thiazepine7
(oil); melting point HCl salt: 250 C (dec.).
2-dimethylamino-7-hydroxy-9-methyl-1,2,3,4-tetrahydro-9H-tri-
benzo(b,d,f)-azepine, (oil).
2-dimethylamino-9,12-dimethyl-1,2,3,4-tetrahydro-9H-tribenzo
(b~d,f)-azepine, (oil).
2-dimethylamino-9-methyl-11-trifluoromethyl-1,2~3~4-tetrahydro-
9H-tribenzo(b,d,f)-azepine, (oil).
Example VII
In the way indicated in example IV are prepared:
2-dimethylamino-1~2~3,4-tetrahydro-9H-tribenzo(b,d,f)-cyclo-
heptatriene; melting point maleate: 145-150C and 169-
171C
2-dimethylamino-12-methoxy-1~2~3~4-tetrahydro-9H-tribenzo
(b,d,f)-cycloheptatriene; m.p. HCl salt: 210C.
2-dimethylamino-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo
(b,d,f)-cycloheptatriene; m.p. maleate: 198-201C.
2-dimethylamino-7-chloro-1,2,3,4-tetrahydro-9H-tribenzo
(b,d,f)-cycloheptatriene, (oil).
2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point maleate: 103-108C.
2-dimethylamino-11-methyl-1,2,3 7 4-tetrahydro-tribenzo(b,d,f)-
oxepine; melting point maleate: 140-142C.
2-dimethylamino-11,12-dimethyl-1,2,3,4-tetrahydro-tribenzo
(b,d,f)-oxepine~ (oil).
- 24 -
1051877
2-dimethylamino-12-chloro-1~2~3~4-tetrahydro-tribenzo(b 7 d, L ) -
_ oxepine; melting point maleate: 195-196C.
2-dimethylamino-6-methyl-1,2,3,4-tetrahydro-tribenzo(b,d 9 f)-
oxepine; melting point maleate: 182-183C.
2-dimethylamino-11-methyl-12-methoxy-1,2~3~4-tetrahydro-9H-
tribenzo(b,d,f)-cycloheptatriene, (oil).
2-morpholino-1,2,3,4-tetrahydro-9~-tribenzo(b,d,f)-cyclo-
heptatriene, (oil).
2-piperidino-3-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-
azepine, (oil).
2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d~f)-thiepine;
melting point HCl salt: 250-255C.
2-dimethylamino-9-methyl-1~2~3,4-tetrahydro-9H-tribenzo
(b,d,f)-azepine; melting point maleate: 210-220C (dec.).
2-dimethylamino-11-trifluoromethyl-1,2,3,4-tetrahydro-triben-
zo(b,d~f)-oxepine, (oil).
2-dimethylamino-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine,
(oil).
Example VIII
In the way indicated in example V, the following compounds
are prepared:
2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point maleate: 198-200C.
2-methylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine,
(oil).
2-morpholino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine,
(oil).
2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point maleate: 105-110C.
10511~77
2-dimethylamino-1,2~3,4-tetrahydro-9H-tribenzo(b,d~f)-cyclo-
heptatriene; melting point maleate: 145-150C (and 168-
170C)
2-dimethylamino-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo
(b,d,f)-cyclohept~triene; melting point maleate: 198-200C.
2-dimethylamino-12-hydroxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d~f)-
cycloheptatriene, (oil).
2-dimethylamino-11-methyl-1,2,3,4-tet ahydro-tribenzo(b,d,f)-
oxepine; melting point maleate: 138-142C.
2-amino-11-methyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine;
melting point maleate: 190-193C.
2-pyrrolidino-1,2,3,4-tetrahydro-9H~tribenzo(b~d~f)-cyclohep-
tatriene, (oil).
2-diethylamino-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-
cycloheptatriene; melting point maleate: 187-192C.
2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine;
melting point maleate: 178-180C.
2-dimethylamino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine;
melting point HCl salt: 250C (dec.).
2-dimethylamino-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-
azepine; melting polnt maleate: 210-228C (dec.).
2-dimethylamino-12-trifluoromethyl-1,2~3,4-tetrahydro-9H-tri-
benzo(b,d,f)-cycloheptatriene, (oil).
Example IX
2-dimethvlamino-1~2~3~4-tetrahydro-tribenzo(b~d~f)-oxePine
1.7 g of 2-amino-1,2,3,4-tetrahydro-tribenzo(b,d,f)-
oxepine is dissol~ed in 47.2 ml of formic acid and 47.2 ml
of a 40% solution of formaldehyde in water. The mixture is
heated at 100C for 5 hours after which the mixture is
- 26 -
105~877
cooled. The solution is then poured into water and made
alkaline with diluted sodiumhydroxide. After that the
mixture is extracted with ether and the ether layers
obtained dried and evaporated. The oil obtained crystal-
lizes with maleic acid as maleate: melting point 103-108C.
Obtained in this manner: 53%.
Example X
2~dimethylamino-12-methoxv-1,2,3,4-tetrahydro-9H-tribenzo
(b,d.f)-cyclohePtatriene
To a solution of 1 g of 2-amino-12-methoxy-1,2,3,4-
tetrahydro-9H-tribenzo-cycloheptatriene in 15 ml of ace-
tonitril, 2.7 ml of a 40% formaldehyde solution in water
and 660 mg of cyanoborohydride are added. The reaction is
exothermic. After stirring for one hour 0.8 ml of acetic
acid is added after which the mixture is stirred for an-
other 2 hours. The solution is made alkaline after that
and then extracted with ether. The ether layer is dried
and e~aporated. Melting point HCl salt: 210C.
~~~ Example XI
~ 2-dimethylaminoethyl-1,2,3.4-tetrahydro-9H-trib _ zo(b,d.f)-
I' cydloheptatriene
~_ J 22.50 g of triethylphosphonoacetate (prepared by means
of the Michaelis-Arbuzow reaction) is added dropwise at
20C to a slurry of 50% sodium hydride (4.9 g) in 200 ml
of dry 1,2-dimethoxy-ethane. After addition the reaction
mixture is stirred for 1 hour at room temperature until
gas evolution ceased. Then 26 g of 2-keto-1,2,3,4-tetra-
hydro-9H-trlbenzo(b,d,f)-cycloheptatriene is added slowly
- 27 -
1051877
at such a rate that the temperature is maintained below
40C. After an additional quarter of an hour the mixture
is poured into a large excess of water and the aqueous
solution extracted with ether. The ether layer after belng
dried over sodiumsulphate and evaporated gives 26.0 g of
2-ethoxycarbonylmethyl-3~4-dihydro-9H-tribenzo(b,d~f)-
cycloheptatriene.
Catalytic hydrogenation of lS g of t~is product in
methanol and palladium/charcoal-catalyst gives the 1,2,3,4-
tetrahydro-compound. After evaporation of the methanol to a
volume of 70 ml, the mixture is treated ~ith 30 g of dimethyl-
amine in an ampoule at 100C for 14 hours to give the 2-di-
methylamino-carbonylmethyl-compound, 13.5 g. This product
is reduced with 15 g lithiumaluminiumhydride in ether (8
hours at boiling temperature) in the usual manner yielding
13.0 g of the title compound. The oily residue is converted
to the maleate, melting point 131-133C.
The same product is obtained by carrying out the hydro-
genation with palladium on charcoal in the last step of the
synthesis instead of performing this hydrogenation previous
to the amide formation and subsequent reduction ~f the amide
moiety with LiAlH4.
In the same manner are prepared:
2-dimethylaminoethyl-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo
(b,d,f)-azepine and
2-aminoethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.
Example XII
2-aminomethvl-1 2,3,4-tetrahvdro-9H-tribenzo(b.d.f)-cvclo-
heptatriene
1.4 g of the 2-cyano-compound, prepared in a similar
- 28 -
1~15~877
manner as described (see '7starting materials" 6) is dissolved
in 50 ml tetrahydrofuran after which 1.5 g LiAlH4 is added.
The mixture is boiled for 4 hours~ After cooling 12 ml of
water is added slowly while stirring. Filtration and evap-
oration of the solvent yields 2.4 g of the 2-aminomethyl-
compound as an oil. Melting point maleate salt: 125-13?C.
In the same manner are prepared:
2-aminomethyl-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.
2-aminomethyl-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-
azep~ne.
2-aminomethyl-7-methoxy-10-chloro-1,2,3~4-tetrahydro-9H-tri-
benzo(b,d,f)-cycloheptatriene.
~ ~' Example XIII
1~ 2-d~methylaminomethyl-1.2,3,4-tetrahydro-tribenzo(b,d~f)-
oxe~ine
/ 1.5 g of 2-cyano-1,2,3,4-tetrahydro-tribenzo(b,d,f)-
oxepine ("starting material 6") is suspended in 80 ml
diethyleneglycol and 65 ml of an aqueous KOH solution
(40%). The mixture is refluxed for 5 hours. After cooling
the mixture to ambient temperature, it is poured into 450
ml water. The aqueous mixture is extracted with ether to
remove non-acidic material. The water-phase is acidified
to about pH 3, whereupon the mixture is extracted with
ether. The ether extracts are washed, dried and then
evaporated, yielding 0.80 g of the crude 2-carboxy-
1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine. This
carboxyl-compound is converted into the dimethylamide
in the usual manner and then reduced with LiA1~4, yielding
0.5 g of the tltle product as an oil.
- 29 -
105187 7
In the same manner are prepared:
2-dimethylaminomethyl-9-methyl-1,2,3,4-tetrahydro-9H-tri-
benzo(b,d,f)-azepine, (oil).
2-dimethylaminomethyl-1,2,3,4,-tetrahydro-9H-tribenzo
(b,d,f)-cycloheptatriene, (oil).
2-aminomethyl-1,2~3,4-tetrahydro-9H-tribenzo(b,d~f)-
cycloheptatriene, (oil).
2-benzylaminomethyl-9-methyl-1~2~3~4-tetrahydro-9H-tri-
benzo(b,d,f)-azepine, (oil).
Example XIV
2-aminoethyl-112,3,4-tetrahydro-9H-tribenzo(b d~f ? -cyclo-
hePtatriene
Diborane gas, oDtained from 1.2 g of NaBH4 and 5.2 ml
of BF3-etherate is let in into a solution of 200 mg of 2-
cyanomethylidene-1~2~3~4-tetrahydro-9H-tribenzo(b~d~f)-
cycloheptatriene (obtained in a similar manner as described
in "Starting materials" 7) in 15 ml THF under nitrogen at-
mosphere.
After that the mixture is refluxed for 1 hour. The
excess of B2H5 present is then decomposed by adding ethanol,
whereupon the solution is evaporated.
The residue is dissolved in 18 ml of a mixture of con-
centrated HCl and water (1:1) whereupon the solution is
heated for some time. The acidic water layer is c~oled
dcwn, made alkaline and then extracted into ether.
Evaporating the solvent yields 85 mg of the title compound
as an oil.
In the same manner are prepared:
2-aminomethyl-1~2,3,4,tetrahydro-tribenzo(b,d,f)-oxepine.
2-aminomethyl-1,2,3,4-tetrahydro-9H_tribenzo~b,d,f)-azepine.
- 30 -
- lOS1877
Example XV
2-amino-1,2,3,4 4a,13b-hexahydro-9H tribenzo(b,d,f?-c~clo-
heptatriene
10 g of 2-keto-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-
cycloheptatriene is suspended in 400 ml of ethanol andsubsequently 20 g hydroxylamine ~Cl and 40 ml pyridine
are added. After refluxing the mixture for 30 minutes,
the mixture is concentrated to a thin oil in ~acuo, from
which the oxime crystallized slowly. The precipitate is
sucked off and washed with water. The dried oxime is sus-
pended in isopropanol. O~er a period of 3 hours 20 g sodium
are added while stirring. The reaction mixture is concen-
trated to l/4 of its volume by evaporation (Rotavap) and
then diluted with water and extracted with ether. The
ether extract was dried over anhydrous potassium carbonate
and finally evaporated to dryness. The oil obtained is
converted into its maleate, meltlng point 212-213C.
Yield 7.3 g.
In the same way are prepared:
2-amino-1,2,3,4,4a,13b-hexahydro-tribenzo(b,d,f)-oxepine
and 2-amino-9_methyl-1,2,3,4,4a,l3b-hexahydro-9H-tribenzo
(b,d,f)-azepine.
By using palladium on charcoal (10%) the ox~me is
hydrogenated into the 4a,13b-unsaturated compound:
2-amino-1~2~3~4-tetrahydro-9H-tribenzo(b,d,f)-cyclohepta-
triene, (oil); meltin~ point maleate: 181-186C.
Example XVI
2-dimethylamino-1,2?3,4?4a,13b-hexa~ dro-gH-tribenzo(b,d,f)-
cycloheptatriene
4 g of the primary amine prepared accordln~ to example
- 31 -
1051877
XV is methylated with a formaldehyde/formic acid mixture (l:i)
during S hours at 100C , (Clarke-Eschweiler procedure).
Obtained is 4.2 g of the dimethylamino product which is
converted to its hydrochloride, melting point 256-263C.
s
Example XVII
2-dimethylamino-1,2~3,4,4a,13b-hexahydro-9H-tribenzo(b,d f)-
cyc lohePtatriene
In the same manner as described in Example IV the compound
2-keto-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cyclohepta-
triene, obtained by oxydation of the corresponding alcohol with
chromic acid ln benzene, acetic acid, water at room temperature,
is reacted with dimethylamine and formic acid in dimethylforma-
mide at reflux temperature. Melting point HCl salt 260-263C.
The same product is obtained by converting 2-hydroxy-
1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cycloheptatriene,
obtained by hydrogenating the corresponding 2-keto-1,2,3,4-
tetrahydro-compound with PtO2 in glacial acetic acid, into
2-mesyloxy-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-
cycloheptatriene in the same manner as described in "starting
materials" 3 and 4 and treating this mesyloxy compound with
dimethylamine.
In the same manners are prepared:
2-dimethylamino-1,2,3,4,4a,13b-hexahydro-tribenzo(b,d,f)-
oxepine.
2-dimethylamino-9-methyl-1,2,3,4,4a,13b-hexahydro-9H-tri-
benzo(b,d,f)-azepine.
30 2-dimethylamino-1,2,3,4,4a,13b-hexahydro-tribenzo(b,d,f)-
~ ie~ai~ c
.
- 32 -
105~877
2-dimethylamino-12-methyl-1,2,3,4,4a,13b-hexahydro-9H-tri-
benzo~b,d,f)-cycloheptatriene.
2-methylamino-1,2,3,4,4a,13b-hexahydro-tribenzo(b,d,f)-
oxepine.
2-dimethylamino-7-methoxy-9-methyl-1,2,3,4,4a,13b-hexahydro-
9H-tribenzo(b,d,f)-azepineO
2-morpholino-9-methyl-1,2,3,4,4a,13b-hexahydro-9H-
tribenzo(b,d,f)-azepineO
Example XVIII
2-aminomethyl-1,2,3,4,4a,13b-hexahydro-9H-tribenzo~b,d,f)-cycloheptatriene
2-hydroxy-1,2,3,4,4a,13b-hexahydro-9H-tribenzo(b,d,f)-cyclo-
heptatriene is converted into the corresponding 2-mesyloxy compound in the
same manner as described in "starting materials" 4 and then treated with
sodiumcyanide, to obtain the 2-cyano-compound. This compound is immediately
reduced with LiAlH4 in ether as described previously, yielding the 2-amino-
methyl-compound as an oilO
Conversion of this oil with maleic acid yields the maleate; melting point:
128 - 132C.
In the same manner is prepared:
2-aminomethyl-9-methyl-1,2,3,4,4a,13b-hexahydro-9H-tribenzo
(b,d,f)-azepineO
- 33 -
