2-BENZYL-PERHYDROAZEPINS, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL PRODUCTS CONTAINING THEM

2-BENZYL-PERHYDROAZEPINES, PROCEDE DE PRODUCTION ET PRODUITS PHARMACEUTIQUES LES CONTENANT

English Abstract

Abstract of the Disclosure
This invention relates to 2-benzyl-perhydroazepines of the general
formula I
<IMG> (I),
in which R1 is a hydrogen atom, an aliphatic or alicyclic hydrocarbon
radical, a cycloalkylalkyl group or an aralkyl group, R2, R3, R4 and R5 are
the same or different and signify a hydrogen atom, a halogen atom, an alkyl
group, a hydroxy group, an alkoxy group, an acyloxy group, an optionally
substituted amino group, a nitro group, an optionally substituted phenyl
group, R1 not being methyl if R2, R3, R4 and R5 mean hydrogen, and their acid
addition salts. This invention also relates to a process for the preparation
of these compounds from known materials. The compounds of formula (I) and
their pharmacologically compatible acid addition salts are useful in human
and veterinary medicine because they produce central stimulation, an increase
in vigilance, promote normal and pathologically inhibited drive of warm-blood
animals. In addition some representatives display a strong analgesic action
or an action which influences the blood pressure.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of 2-benzyl-perhydroaze-
pines of the general formula I*
<IMG> (I*)
in which R1* signifies a hydrogen atom, a straight-chained or
branched aliphatic hydrocarbon radical with 1 to 6 carbon atoms,
a cycloalkylalkyl group with 1 or 2 carbon atoms in the alkyl
radical and 3 to 5 carbon atoms in the cycloalkyl radical, or a
phenylalkyl group with 1 to 4 carbon atoms in the alkyl radical,
optionally monosubstituted by halogen or by alkyl or alkoxy with
1 to 4 carbon atoms in the alkyl moiety,
R2*, R3*, R4* and R5* signify a hydrogen atom, a hal-
ogen atom, a hydroxy group, an alkyl group with 1 to 4 carbon
atoms, an alkoxy group with 1 to 4 carbon atoms, an alkanoyloxy
group with 2 to 5 carbon atoms, an amino group, an alkanoylamino
group with 2 to 5 carbon atoms, a dialkylamino group with 1 to 2
carbon atoms in each alkyl radical, a nitro group or a phenyl
group which may be substituted in the para position, by halogen,
hydroxy, alkyl or alkoxy with 1 to 4 carbon atoms in the alkyl
moiety, provided that R1* is not methyl if R2*, R3*, R4* and R5*
all represent hydrogen,
and their pharmaceutically compatible acid addition salts; wherein
either
A) a 2-benzyl-azacycloheptane of the general formula II*
72

<IMG> (II*)
in which R2*, R3*, R4* and R5* have the meanings given above and
<IMG>
signifies one of the groupings
<IMG>
(a) (b) (c) and (d)
R6 is as defined for R1* other than hydrogen, and R7 is as def-
ined for R1* other than phenylalkyl, is reduced; or
B) a 2-benzyl-azacycloheptane of the general formula III
<IMG> (III)
wherein R7 is as defined above, is subjected to functionalisation
effected as follows:
1) introduction of one or two nitro groups by nitra-
tion of compounds (III) wherein Gn denotes hydrogen,
2) introduction of one or two amino groups by reduc-
tion of compounds (III) wherein Gn denotes one or two nitro groups,
3) introduction of one or two halogen atom(s) by
nucleus halogenation of compounds (III) wherein Gn denotes hydro-
gen,
4) introduction of hydroxy group(s) by ether splitting
73

of compounds (III) wherein Gn denotes 1 to 4 alkoxy groups,
5) introduction of alkoxy groups by etherification
of compounds (III) wherein G denotes hydroxy and n denotes 1 to 4,
6) introduction of one or two acylamino or acyloxy
group(s) by acylation of compounds (III) wherein Gn denotes amino
or hydroxy group(s),
7) liberation of one or two hydroxy or amino group(s)
by saponification of compounds (III) wherein Gn denotes one or
two acyloxy or acylamino group(s); or
C) a N-acyl-2-benzylazacycloheptane of the general formula
IV*
<IMG> (IV*)
in which R2*, R3*, R4* and R5* have the meaning given above and
R8 signifies an aliphatic or alicyclic hydrocarbon radical, a
cycloalkylalkyl radical, an optionally substituted phenyl radical
or phenalkyl radical, is reduced and where necessary N-dealkyl-
ated and if required N-substituted with a hydrocarbon radical as
defined for R1*; or
D) hydrolysing and decarboxylating a 2-benzyl-azacyclo-
heptane of the general formula
<IMG> (IIIa)
where Q is an alkoxycarbonyl group and R2*, R3*, R4* and R5* are
as defined above;
and where required the base obtained is converted into a pharma-
ceutically compatible acid addition salt, or a salt obtained is
converted into the free base.
74

2. A process for the production of 2-benzyl-perhydroaze-
pines of the general formula I*
<IMG> (I*)
in which R1* signifies a hydrogen atom, a straight-chained or
branched aliphatic hydrocarbon radical with 1 to 6 carton atoms,
a cycloalkylalkyl group with 1 or 2 carbon atoms in the alkyl
radical and 3 to 5 carbon atoms in the cycloalkyl radical, or a
phenylalkyl group with 1 to 4 carbon atoms in the alkyl radical,
optionally monosubstituted by halogen or by alkyl or alkoxy with
1 to 4 carbon atoms in the alkyl moiety, R2 signifies a halogen
atom, a hydroxy group, an alkyl group with 1 to 4 carbon atoms,
an alkoxy group with 1 to 4 carbon atoms, an alkanoyloxy group
with 2 to 5 carbon atoms, an amino group, an alkanoylamino group
with 2 to 5 carbon atoms, a dialkylamino group with 1 to 2 carbon
atoms per alkyl radical, a nitro group or a phenyl group which
may be substituted in the para position, by halogen, hydroxy, al-
kyl or alkoxy with 1 to 4 carbon atoms in the alkyl moiety,
R3*, R4* and R5* signify a hydrogen atom, a halo-
gen atom, a hydroxy group, an alkyl group with 1 to 4 carbon atoms,
an alkoxy group with 1 to 4 carbon atoms, an alkanoyloxy group
with 2 to 5 carbon atoms, an amino group, a dialkylamino group
with 1 to 2 carbon atoms in each alkyl radical, or a nitro group,
at least one of the substituents at 2 or 6 position in the benzyl
group representing a hydrogen atom, and their pharmacologically
compatible acid addition salts; wherein either
A) a 2-benzyl-azacycloheptane of the general formula II*

<IMG> (II*)
in which R2*, R3*, R4* and R5* have the meanings given above and
<IMG>
signifies one of the groupings
<IMG>
(a) (b) (c) and (d)
R6 is as defined for R1* other than hydrogen, and R7 is as def-
ined for R1* other than phenylalkyl, is reduced; or
B) a 2-benzyl-azacycloheptane of the general formula III
<IMG> (III)
wherein R7 is as defined above, is subjected to functionalisation
effected as follows:
1) introduction of one or two nitro groups by nitra-
tion of compounds (III) wherein Gn denotes hydrogen,
2) introduction of one or two amino groups by reduc-
tion of compounds (III) wherein Gn denotes one or two nitro groups,
3) introduction of one or two halogen atom(s) by
nucleus halogenation of compounds (III) wherein Gn denotes hydro-
gen,
4) introduction of hydroxy group(s) by ether splitting
76

of compounds (III) wherein Gn denotes 1 to 4 alkoxy groups,
5) introduction of alkoxy groups by etherification
of compounds (III) wherein G denotes hydroxy and n denotes 1 to 4,
6) introduction of one or two acylamino or acyloxy
group(s) by acylation of compounds (III) wherein Gn denotes amino
or hydroxy group(s),
7) liberation of one or two hydroxy or amino group(s)
by saponification of compounds (III) wherein Gn denotes one or two
acyloxy or acylamino group(s); or
C) a N-acyl-2-benzyl-azacycloheptane of the general formula
IV*
<IMG> (IV*)
in which R2*, R3*, R4* and R5* have the meaning given above and
R8* signifies an aliphatic or alicyclic hydrocarbon radical, a
cycloalkylalkyl radical, an optionally substituted phenyl radical
or phenalkyl radical, is reduced and where necessary N-dealkylated
and if required N-substituted with a hydrocarbon radical as de-
fined for R1*;
and where required the base obtained is converted into a pharma-
ceutically compatible acid addition salt; or a salt obtained is
converted into the free base.
3. A process for the preparation of a 2-benzyl-perhydro-
azepine of the general formula I*
<IMG> (I*)
or a pharmacologically compatible acid addition salt thereof, in
77

which R1* is as defined in claim 1, R2*, R3*, R4* and R5* are
the same or different and each signifies a hydrogen atom, a halo-
gen atom, an alkyl group of 1 to 4 carbon atoms, a hydroxy group,
an alkoxy group of 1 to 4 carbon atoms, an alkanoyloxy group of
2 to 5 carbon atoms, an amino group, an alkanoylamino group of
2 to 5 carbon atoms,
78

a dialkyamino group of 1 to 2 carbon atoms per alkyl radical, a nitro group
or a phenyl group optionally substituted in the p-position by halogen, hydroxy,
alkyl or alkoxy of 1 to 4 carbon atoms in the alkyl moiety, R1* not being
methyl if R2*,R3*,R4* and R5* all have the meaning of hydrogen, but including
the pharmacologically compatible acid addition salts of this base, which
comprises either:
A) reducing a 2-benzyl-azacycloheptane of the general formula II*:
<IMG> (II*)
in which R2*,R3*,R4* and R5* are as defined above and the
<IMG>
signifies one of the groupings
<IMG>
(a) (b) (c) or (d)
in which R6 and R7 are as defined in claim 1; or
B) hydrolyzing and decarboxylating a 2-benzyl-azacycloheptane of
the general formula
<IMG> (IIIa)
wherein Q is an alkoxycarbonyl group and R2*,R3*,R4* and R5* are as defined
above; or
79

C) reducing an N-acyl-2-benzyl-azacycloheptane of the
general formula IV*
<IMG> (IV*)
in which R2*, R3*, R4* and R5* are as defined above and R8* is as
defined in claim 1; and where any one of process steps A to C
can be followed by one or more of the following additional process
steps:
D) alkylating, alkenylating, cycloalkylalkylating or
phenylalkylating a compound of formula (I*) obtained in which R1*
is a hydrogen atom to produce a corresponding compound of formula
(I*) in which R1* is alkyl, alkenyl, cycloalkylalkyl or phenyl-
alkyl as defined;
DD) N-dealkylating, -dealkenylating, -decycloalkylalkylat-
ing, or -dephenylalkylating a compound of formula (I*) so obtain-
ed in which R1* is alkyl, alkenyl, cycloalkylalkyl or phenylalkyl
to produce a corresponding compound of formula (I*) in which R1*
is hydrogen; or
E) nitrating a compound Of formula (I*) obtained in which
one or both of R2* and R3* are hydrogen atoms and R4* and R5* are
both hydrogen atoms to produce a corresponding compound of formula
(I*) in which one of R2* and R3* is a nitro group, the other being
hydrogen or nitro, and R4* and R5* are both hydrogen atoms; or
F) reducing a nitro compound of formula (I*) obtained to
produce a corresponding amino compound of formula (I*);
G) alkylating a compound of formula (I*) obtained in which
one or two of R2*, R3*, R4* and R5* is an amino group to produce

a corresponding mono- or di-alkyl-amino compound of formula (I*);
H) acylating a compound of formula (I*) obtained in which
one or two of R2*, R3*, R4* and R5* is an amino group to produce
a corresponding acylamino compound of formula (I*);
I) halogenating a compound of formula (I*) obtained in
which one or two of R2 , R3 , R4 and R5 is a hydrogen atom to
produce a corresponding compound of formula (I*) in which one or
two of R2*, R3*, R4* and R5* is a halogen atom; or
K) dealkylating or deacylating a compound of formula (I*)
obtained in which one or two of R2*, R3*, R4* and R5* is an
alkoxy or acyloxy group to produce a corresponding compound of
formula (I*) in which one or two of R2*, R3*, R4* and R5* is a
hydroxy group; or where any of steps (A) to (K) can be followed
by the further step of converting a base of formula (I*) into
a pharmacologically compatible acid addition salt.
4. A process according to claim 3(C) in which the starting
material of formula (IV*) is prepared by acylating a corresponding
N-substituted compound.
5. A process according to claim 3 in which a compound of
formula (I*) obtained in which R1* is benzyl is subjected to hy-
drogenolysis to produce a corresponding compound of formula (I*)
in which R1* is a hydrogen atom.
6. A process according to claim 3(B) in which the start-
ing material of formula IIIa is prepared by reacting a corres-
ponding N-methyl or N-benzyl compound with an alkyl chloroformate.
7. A process according to claim 3 in which R1* signifies
a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, an al-
kenyl group of 2 to 6 carbon atoms, a cycloalkylalkyl group in
which the cycloalkyl moiety has 3 to 5 carbon atoms and the alkyl
moiety has 1 to 2 carbon atoms or a phenyl-alkyl group in which
81

the alkyl moiety has 1 to 4 carbon atoms and the phenyl group is
either unsubstituted or substituted by a fluorine, chlorine or
bromine atom, R2* signifies a hydrogen, fluorine, chlorine or
bromine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, an amino
group, a dialkylamino group with 1 to 2 carbon atoms per alkyl
radical, a C2 to C5 alkanoylamino group, a hydroxy group or a
nitro group, R3* signifies hydrogen, hydroxy or C1-C4 alkoxy,
and R4* and R5* signify hydrogen atoms.
8. A process according to claim 3 in which R1* signifies
a hydrogen atom or a methyl, ethyl, isopropyl, n-hexyl, sec-
butyl, neopentyl, allyl, cyclopropylmethyl, benzyl or 4-(4-
fluorophenyl)butyl group, R2* signifies a hydrogen, chlorine or
bromine atom, a methyl, methoxy, nitro, amino, diethylamino,
acetylamino or hydroxy group, R3* signifies a hydrogen atom or
a methoxy or hydroxy group, and R4* and R5* signify hydrogen
atoms.
9. A process according to claim 3 in which R1 is methyl,
R2* is chlorine in the 2-position and R3*, R4* and R5* are hydro-
gen atoms.
10. A process nor the preparation of 2-(2-chlorobenzyl-1-
methyl-perhydroazepine and its picrate which comprises reducing
2-[2-chlorobenzylidene]-1-methyl-perhydroazepine and when the
picrate is required reacting the base so obtained with picric acid.
11. A process according to claim 3 in which R1*, R3*, R4*,
and R5* are hydrogen atoms and R2* is a chlorine atom in the 4-
position.
12. A process for the preparation of 2-(4-chlorobenzyl)-
perhydroazepine and its hydrochloride which comprises reducing
2-(4-chlorobenzyl)-4,5,6,7-tetrahydro-3H-azepine, 7-(4-chloro-
benzyl)-perhydroazepine-2 one or 2-(4-chlorobenzyl)-N-nitroso-
82

perhydroazepine or hydrolysing and decarboxylating 1-ethoxycar-
bonyl-2-(4-chlorobenzyl)perhydroazepine and when the hydrochlor-
ide is required reacting the base so obtained with hydrogen
chloride.
13. A process for the preparation of 2-(4-chlorobenzyl)-
perhydroazepine and its hydrochloride which comprises subjecting
1-benzyl-2-(4-chlorobenzyl)-perhydroazepine to hydrogenolysis and
when the hydrochloride is required reacting the base so obtained
with hydrogen chloride.
14. A process according to claim 3 in which R1* is iso-
propyl, R2* is a chlorine atom in the 4-position and R3*, R4* and
R5* are hydrogen atoms.
15. A process for the preparation of 2 (4-chlorobenzyl)-1-
isopropylperhydroazepine which comprises isopropylating 2-(4-
chlorobenzyl)perhydroazepine.
16. A process according to claim 3 in which R1* is methyl,
R2* is a chlorine atom in the 4-position and R3*, R4* and R5* are
hydrogen atoms.
17. A process for the preparation of 2-(4-chlorobenzyl)-1-
methyl-perhydroazepine and its picrate, hibenzate, citrate,
fumarate, benzoate, maleate and embonate which comprises reducing
2-(4-chlorobenzylidene)-1-methyl-perhydroazepine and when the
stated salts are required reacting the base so obtained with
picric, hibenzic, citric, fumaric, benzoic, maleic or embonic acid.
18. A process according to claim 3 in which R1*, R3*, R4*
and R5* are hydrogen atoms and R2* is an amino group in the 4-
position.
19. A process for the preparation of 2-(4-aminobenzyl)-
perhydroazepine and its benzoate which comprises reducing 2-(4-
83

nitrobenzyl)perhydroazepine or 7-(4-aminobenzyl)perhydroazepin-
2-one and when the benzoate is required reacting the base so ob-
tained with benzoic acid.
20. A process according to claim 3 in which R1*, R2*, R3*,
R4* and R5* are hydrogen atoms.
21. A process for the preparation of 2-benzylperhydro-
azepine and its hydrochloride which comprises reducing 2-benzyl-
4,5,6,7-tetrahydro-3H-azepine and when the hydrochloride is
required reacting the base so obtained with hydrogen chloride.
22. A process according to claim 3 in which R1* is cyclo-
propylmethyl and R2*, R3*, R4* and R5* are hydrogen atoms.
23. A process for the preparation of 2 benzyl-1-cyclo-
propylmethylperhydroazepine which comprises reducing 2-benzyl-
1-cyclopropylcarbonylperhydroazepine.
24. 2-Benzyl-perhydroazepines of the general formula I*
defined in claim 1, and their pharmaceutically compatible acid
addition salts, when prepared by the process of claim 1 or by
an obvious chemical equivalent thereof.
25. 2-(2-Chlorobenzyl)-1-methyl-perhydroazepine and its
picrate, when prepared by the process of claim 10 or by an obvious
chemical equivalent thereof.
26. 2-(4-Chlorobenzyl)-perhydroazepine and its hydro-
chloride, when prepared by the process of claim 12 or 13 or by
an obvious chemical equivalent thereof.
27. 2-(4-Chlorobenzyl)-1-isopropyl-perhydroazepine, when
prepared by the process of claim 15 or by an obvious chemical
equivalent thereof.
28. 2-(4-Chlorobenzyl)-1-methyl-perhydroazepine and its
84

picrate, hibenzate, citrate, fumarate, benzoate, maleate and em-
bonate, when prepared by the process of claim 17 or by an obvious
chemical equivalent thereof.
29. 2-(4-Aminobenzyl)-perhydroazepine and its benzoate,
when prepared by the process of claim 19 or by an obvious
chemical equivalent thereof.
30. 2-Benzyl-perhydroazepine and its hydrochloride, when
prepared by the process of claim 21 or by an obvious chemical
equivalent thereof.
31. 2-Benzyl-1-cyclopropylmethyl-perhydroazepine, when pre-
pared by the process of claim 23 or by an obvious chemical equiv-
alent thereof.
32. A process for the preparation of 1-allyl-2-(4-chloro-
benzyl)-perhydroazepine which comprises allylating 2-(4-chloro-
benzyl)-perhydroazine.
33. 1-Allyl-2-(4-chlorobenzyl)-perhydroazepine, when
prepared by the process of claim 32 or by an obvious chemical
equivalent thereof.

Description

? ~
The invention relates to 2-benzyl-perhydroazeplnes which may also be
substituted ~H.Y-or more times in the phenyl ring, a process for their prepara-
~ion and pharmaceutical compositions containing them.
In the course of work regarding elimination reactions L.P.A. Fery
and L. Wilputte-Steinert report ~Bull. Soc. Chim. Belg. 73 (196~) 154 - 165)re~
garding the formation of l-methyl-2-benzylhe~amethylenimine, without this com-
pound being allocated an action. The formation of the compound only took
place in such a small quantity that it could be identified only as a derivative
in the form of the picrate and methoiodide.
In German Offenlegungsschrift ~Published Specification) DE-OS
2 548 053 saturated ~-substituted benzyl-l-benzhydrylazaheterocyclic compounds
are claimed, but only ~-substituted benzyl-l-benzhydrylazetidines are des-
cribed, which are intended for use for the treatment of obesity. It has now
been found that optionally substituted 2-benzylperhydroazepines possess valu-
able pharmalogical properties which can be utilised commercially.
The invention relates to 2-benzyl-perhydroazepines of the general
formula I ~-
~ '
~ CHz ~, R3 (1~,
R R4
: R5
- 2 -

3'~
in ~rhich R1 is a hydrosen atom, an aliphatic or alicyclic
hydrocarbon radical, a cycloalkylall~yl gro~lp or an aralkyl
group,
R2, R3, R4 and R5 are the same or different and ~ignify
a hydrogen atom, a halogen atom, an al'kyl group, a hydroxy
~roup, an alkoxy group, an acyloxy group, an optionally
substituted amino group, a nitro group, an optionally sub-
stituted phenyl group, R not being methyl if R , R3, R
and R mean hydrogen, and their acid addition salts.
: ,
Aliphatic hydrocarbon radicals one include straight-
chained or branched alkyl radicals wi*h 1 to 7 carbon atoms
or all~enyl and alkinyl radicals with 2 to 7 carbon atoms.
Straight-chained alkyl radicals are the methyl, ethyI,
propyl, butyl, pentyl, hexyl or heptyl radicals, of ~hich
those with 1 to 6, especially those with 1 to 3, carbon
atoms are preferred~ An alkenyl radical is, e.g., the
allyl radical. An alkinyl radical is, e.g., the propinyl
radical. Branched alkyl radicals with 3 to 7 carbon atoms
are, for example, the isopropyl, isobutyl, sec.-butyl,
tert.-butyl, 3-methylbutyl, 2,2-dimethylpropyl, 2-methyl-
pentyl, 3,3-dimethylbutyl or 2-ethyl~3-methylbutyl radicals,
of which those with 3 to 5, especially with 3, carbon atoms
are preferred. Alicyclic hydrocarbon radicals ~ff~ ~nclude
.~ .
,~

cycloalkyl radicals with 3 to 7 carbon atoms, for example
the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
cycloheptyl radical, of which those with 5 to 6 carbon
atoms are preferred
As cycloalkylalkyl groups one can use those with
1 to 4 carbon atoms in the alkyl radical and 3 ~o 7 carbon
atoms ln the cycloalkyl radical, of which those with 1 to 2
carbon atoms in the alkyl radical and 3 to 5 carbon atoms in
the cycloalkyl radical are preferred. Selected cycloalkyl-
alkyl groups are the cyclopropylmethyl and the cyclobutyl-
methyl groups.
Preferred aralkyl groups are those with aryl groups
which contain up to 12 carbon atoms and alkyl groups which
contain 1 to 4 carbon atoms, of which those with 6 carbon
atoms in the aryl radical and 1 to 4 carbon atoms in the
alkyl radical, mainly with 1 carbon atom in the alkyl radical,
are preferred. Examples of such groups are the benzyl,
phenethyl and phenylpropyl groups, of which the benzyl group
is preferred. The aralkyl groups can also be substituted,
2Q of which those monosubstituted in the aryl radical are pre-
ferred, including those substituted by halogen atoms, such
as fluorine, chlorine or bromine atoms, alkyl and/or alkoxy
gro~ps with 1 to 4 car~on atoms. Pxamples of such groups
are the p-chlorobenzyl, the m-chlorobenzy~ the p-bromobenzyl,
-- . ~ ~ -

the o-fluorobenzyl, the p,fluorobenzyl, the p-tolyl and the
p-methoxybenzyl groups. Among the aralkyl groups substituted
in the alkyl group the arylhydroxyalkyl and especially the
aryloxoalkyl groups are preferred, and examples of such groups
i are the benzoylmethyl, 2-benzoylethyl, 3-benzoylpropyl groups,
with preference for the 3-~p-chlorobenzoyl)-propyl, especially
the 3-~p-fluorobenzoyl)-propyl group.
~q~ogen 2 3 4 5
halogen atoms R , R , R or R ~M~are fluorine,
chlorine, bromine or iodine, preferably fluorine, chlorine,
. '
bromine and especially chlorine. Preferred alkyl groups or
alkoxy groups R , R3, R4 or R5 are those with 1 to 4 carbon
atoms, of which those with 1 to 3, and especially those with
1 carbon atoms are preferred. Preferred acyloxy groups are
-0-CO-Rl groups in which Rl has the meaning given above, of
which the alkanoyloxy groups with 1 to 7, especially with
a ce~o ~y
2 to 5, carbon atoms, especially the ~s4~ group, are pre-
ferred. Besides the unsubstituted amino group substituents
R , R , R4 or R5 comprise substituted amino groups of which
for example one may mention alkyl and dialkylamino groups
with 1 to ~, preferably 1 or 2, carbon atoms in the alkyl
radical and also acylamino groups with the usual acyl groups
~ used to protect am~no groups, such as alkyanoyl groups with
-` 2 to 5 carbon atoms. The subs~ituents R , R , R or R
.`.~ .
:,
'''

~h~ t
also comprise besides the unsubstituted pheny]. group phenyl
groups which are subs~ituted with halogen atoms, hydroxy, alkyl .:
and/or alkoxy groups ~ith 1 to 4 carbon atoms, of which the
p-substituted phenyl groups, such as p-chlorophenyl, p-fluoro-
phenyl, p-hydroxyphenyl, p-methoxyphenyl groups, are pre~erred.
Salts useful in this invention are those acid addi-
tion salts, which are pharmacologically compatible due to the
fact that they are derived from inorganic and organic acids
having p~ar~acolo~ically compatible anions usually employed in
pharmacy. If pharmacologically incompatible salts are
isolated they are converted into pharmacologically compatible
salts by processes known to the technician. Suitable salts
by way of example are water-soluble and water-insoluble acid
addition salts such as the hydrochloride, hydrobromide,
hydroiodide, phosphate, nitrate, sulphate, acetate, citra~e,
gluconate, benzoate, hibenzate (2-~4-hydroxybenzoyl3-
benzoate), fendizoate (o-/(2'-hydroxy-4-blphenylyl)-carbonyl/-
benzoate), propionate, bu~yrate, sulphosalicylate, maleate,
: laurate, malate, fumarate, succinate, oxalate, tartrate,
amsonate ~4,4~-diamino-stilbene-2,2~-disulphoTIate), embonate
: ~l,l'-methylene-bis-2-hydroxy-3-naphthoate), metembonate,
stearate, tosilate (p-toluenesulphonate), 2-hydroxy-3-
naph~hoate, 3-hydroxy-2-naphthoate, mesilate (methanesul- :~
.- - 6 - :
~ : ,

- 7 ~ 5~
phonate), as ~ell as salts with Bumetanid (3-(butylamino)-
4-phano~y-5-sulphamoyl-benzoic acid), Fuxosemid ~4-chloro-
N-furfuryl-5-sulphamoylanthranilic acid), Besunid (~benzyl-
3-(butylamino)-5-sulphamoyl-benzoic acid), Pir~tanid
4-phenoxy-3-(1-pyrrolidinyl)-5-sulphamoyl-benzoic acid),
Etacrynic acid (~2,3-dichloro-4-(2-methylene-butyryl)-
pheno~y]-acetic acid), Tienilic acid ([2,3-dichloro ~-
(2-thenoyl)-pheno~y~-acetic acid).
~ ne embodiment of the In~ention consists of
2-benzyl-perhydroa~epinesof the general formula Iu
R2~
~FH '~
,: ~
; ~
in ~hich R signifies a hydrogen atom, a straight-chained
'; or branched aliphatic hydrocarbon radical with 1 to 6
carbon atoms, a cycloalkylalkyl group with 1 or 2 carbon
atoms in the alkyl radical and 3 to 5 carbo,n atoms in the
cycloalkyl radical 7 or an optionally monosubstituted
; phenylalkyl group with 1 to 4 carbon atoms in the alkyl
'~
. '
-
'. : '
: .-, . . .
. : '
.

-- 8 --
radical,
R2 signifies a halogen atom, a hyd:rox~ group, an alkyl
group with 1 to 4 carbon atoms I an alkoxy group ~rith 1 to
4 carbon atoms, an alkanoyloxy group with ~ to 5 carbon
atoms, an amino group, a dialkylamino ~sroup with 1 to 2
carbon atoms per alkyl radical, a nitro group or a phenyl
group ~ich may be substituted in the para position,
3~ 4~ 5~
P~ , R and R signify a hydrogen atom, a halogen
atom, a hydro~cy group, an alkyl group ~i th 1 to 4 carbon
atoms, an alkoxy group ~ith 1 to 4 carbon atoms, an
alkanoyloxy group with 2 to 5 carbon atoms, an aminO group,
a dialkylamino group with 1 to 2 carbon atoms per alkyl
radical or a nitro group, at least one of the two substi-
tuents in position 2 or 6 of the benzyl group being a
hydrogen atom,
and their pharmacologically compatible acid addition salts.
Another form of embodiment of the Invention consists
of 2-benzyl-perhydroazepines of the general formula I~
R2~
3~ '
R
R 5 ~
r :-
~ ' :
. ' i
,~ .-, . . . !

_ 9 - '~
1~ C
in wllich R sig~ifies a hydrogen atom, a straight-
chained or branched aliphatic hydrocar'bon radical with 2 `
to 6 carbon atoms, a cycloalkylalkyl sroup with -1 or 2
carbon atoms in the alkyl radical and 3 to 5 carbon atoms
in the cycloalkyl radical or an optionally monosubstituted
phenylalkyl group with 1 to 4 carbon at:oms in the alkyl
radical,
2~ # 1~#~ 5~
R , R' , R and R signify a hydro~en atom, a
halogen atom, a hydroxy group, an allcyl group with 1 to 4
carbon atoms, an alkoxy group with 1 to.4 carbon atoms,
an alkanoyloxy group with 2 to 5 carbon atoms, an amino
group, a dialkylamino group with I to 2 carbon atoms per
alkyl radical, a nitro group or a phenyl group which may
be substituted in the para position,
at least one of the substituen*s at 2 or 6 position of
the benzyl group being a hydrogen atom,
and their pharmacologically compati~le acid addition salts.
Further forms of embodiment of the Invention are those
2-benzyl-perhydroazepine~"of the general formulae I~ or I*~
1~ 2~ * ~ 2# #
in which R , R , R-' , R and R' or else R , R
354 It~ 5~
n , R and R have the meanings given above, in
which at least one., preferably two, of the substituents
3~ ~ 5~ ~* 4~
R , R or R or else R' , R or R' and at least
one of the substituents at 2 or 6 position in the benzyl
.
.
': ' ' ' ~ - ~
.
.,~ . ~ , . ~ .

3~
-- 10 --
` group signify a hydrogen atom, and their pharmacologically
compatible acid addition salts.
Preferred 2-benzyl-perhydroazepines of th2 general formula
I~ are those in which R signifies a hydrogen atom, a
: straight~chained alkyl radical with l to 3 carbon atoms,
a branched alkyl radical with 3 to 5 carbon atoms, a cyclo_
alkylmethyl radical Wit}l 3 to 5 carbon atoms in the
cycloalkyl group or a benzyl radical ~lich may be substi-
tuted in the para position b~ halogen, methyl or methoxy,
R signifies a halogen atom, a hydroxy group, a methoxy
group, an amino group or a nitro group,
. . '1~
R' signifies a hydrogen atom, a halogen atom, a hydroxy
group, a metho~y group, an arnino group or a nitro group,
2~ 3~
in which the substituents R and R are preferably
located at 2, 3 and/or 4 position,
4~ 5
R and R signify a hydrogen atom, and their pharmaco~ogi-
cally compatible acid addition salts.
Selected 2-benzyl-perhydroazepine~ of the formula I~
are those in which R signifies a hydrogen atom, a methyl
... .
group, an isopropyl group, a cyclopropylmethyl group or
a benzyl group,
R2 signifies a halogen atom, a hydroxy group, a methoxy
group, an amino g~oup or a nitro group,
R' signifies a hydrogen atom, a halogen atom, a hydro~y
~ ~ .
.
;,.: .. ' . ' ,, : ' . ' ~ :, ' i,.
- . . ~ ,,
. . : ;
' :' ~ ' " ' ' ~
:: . .: ~, . .:
.. . . .

3~9~
group, a methoxy group, an amino group or a nitro group,
2~ ~
in which the substituents R and R' are preferably
situated at 2, 3 and/or 4 position,
4~ 5~
R and R signify a hydrogen atom, and their pharmacologi-
cally compatible acid addition sa1ts.
: Preferred 2-benzyl-perhydroazepine~ of the general
formula I~ are those in ~hich
R1 signifies a hydrogen atom, a straight-chained
~: alkyl radical with 2 to 3 carbon atoms, a branched alkyl
radical with 3 to 5 carbon atoms, a cycloalkylmethyl radi-
cal with 3 to 5 carbon atoms in the cycloalkyl group, a
benzyl radical, a p-halobenzyl radical, a p-methylbenzyl
radical or a p-methox~benzyl radical,
2~* ~
R and R' are the same or different and signify
- a hydrogen atom, a halogen atom, a hydroxy group, a methoxy
group, an amino gro~p or a nitro group, in which the
2~
~ substituents R and R~ are preferably located at
2, 3 and/or 4 position,
4~ 5~
R and R signify a hydrogen atom, and their pharmaco-
logiGall~ compatihle acid addition salts.
Selected 2-benzyl-perhydroazepines:of the general formula
I~ are those in which
R signifies a hydrog~n a-tom, an ethyl group, an iso-
propyl group, a cyclopropylmethyl group or a benzyl group,
:
,
: . ' ' ' . '
.
' ': . ' : ' ':

'7~
- -12 -
~ # ,~ ~ :
R~ and R' are the same or di~ferent and si~nify
a hydrogen atom, ~ialogen atom, a hydroxy group, a m~thoxy group, an
amino group or a nitro group, in which the substituents
2~
R and R' are preferably located at; 2, 3 and!or 4 po-
sition,
4~ #
`: R and R' signify a hydrogen atom,
- and their pharmaceutically compatihe acid addition salts.
Particularly preferred 2-benzyl-perhydroazepins are
those of the general formula I~, in which
R sisnifies a hydrogen atom, a methyl group, ~n
isopropyl group or a cyclopropylmethyl Sroup,
R2 signifies a chlorine atom at 2, 3 or 4 position,
or an amino group at ~ position,
3~ 5
n , R ~nd R signify a hydrogen atom, and their
pharmacologically compatible acid addition salts7
Selected representatives of the compounds according to
the Invention are
; 2-(2-chlorobenzyl)-l~methyl-perhy~roazepine,
2-(4-chlorobenzyl)-perhydroazepine, .
2-(4-chlorobenzyl)-1-isopropyl-perhydroazepine,
2-(4-chlorobenzyl)-l-methyl-perhydroazepine,
2-benzyl-1-cyclopropylmethyl-perhydroazepine,
2-benzyl-perhydroazepine,
2-(4-aminobenzyl)-perhydroazepine,
,:
. ~, ' ' ~
. ,~
~, : , ::
: .

- 13 ~ L~ f~
and their pharmacologically compatlble acid addition salts.
The 2-benzyl-perhydroazepines a the general -formula I
or I~ and I~ pogsess a chirality centre on the carbon
atom marked with a (~)~ The Invention therefore includes

both the racemates and also the enantiomer~ and their
mixtures.
The optionally substituted 2-benzyl-perhydroazepines of
the seneral formula I or of embodiments I~ and I~ possess
valuable properties which make them commercially utilisableO
On the one hand these compounds and 2-benzyl-1-methyl-per
hydroazepin as well as their pharmacologically, that is
to say biologically, tolerable, salts possess pronounced
pharmacolosical properties, particularly effects on the
central nervous system (CNS), on the blood pressure and
on the sensation of pain of warm-blooded animals, and on
the other hand they can be converted into other 2-benzyl-
perhydroazepines of the ~eneral formula I, and therefore
represent valuable intermediat~ products for the production
of pharmacologically active compounds of the general
formula I or of embodiments I~ a~d I~ as well as their
~iologically tolerable salts.
: The activity on the CNS of 2-benzyl-perhydroazepines and
the pharmacologically tolerable salts extends to central
stimulation, increase .in ~isilance, the promotion of the
: . ..
.
:: ,

normal and patholosically inhibited drive of ~arm-blooded
animals. In addition some representatives d:isplay a
strong analgesic action or an action which influences
the blood pres~urel
The excellent and broad pharmacological efficacy of
the 2-benzyl-perhydroazepines permits of their use both in
human and in veterinary medicine, qhere they are used
for the prophylaxis of disorders or for the treatment of
symptom3 which have already occured.
As indications or use in human medicine one may men-
tion the lack of drive in men and women, a reduction in
vigilance, depression, organic psychosyndromes in cerebral
degeneration processes, lack of performance, blood pressure
disorders and conditions of exhaustion as well as conditions
of pain, in children mental and psychological inhibition
of development as well as difficulties in learning, ~-
So far as veterinary medicine is concerned, the indi-
cations are drop in performance and conditions of pain.
For example it is possible to trea-t higher animals, such
as farm and domestic animals.
/ 1
: .

.
The Invention also relates to pharmaceutical compositions
~hich contain ~-benzyl-perhydroazepins of the general
formula I
.
.~ RZ
11 ~ ~ 4
:~: R5
.
in s~hich R signifies a hydrogen atom, an aliphatic or
. alic~clic hydrocarbon radical, a cycloalkylalkyl group
; or an aralkyl group,
R2, R3, R4 and R5 are the same or different and signify
a hydro$en atom, a halogen atom, an alkyl group, a hydroxy
~: group, an alkoxy group, an acyloxy group, an optionally
: substituted amino group, a nitro group, an optionally sub-
~ stituted phenyl group, and/or their pharmacologically
:~ tolerated acid addition salts.
Preferred pharmaceutical compositions are those ~hich
contain 2-benzyl-perhydroazepins of the embodiments I~
, .
:: :
''~
.,-,- .: : . ,
' : :-' '~ , ,,

- 16 ~ '7~
or I~ or their preferred representatives and/or the
correspondins pharmacologically compatlble acid addition
sRlts .
The pharmaceutical compositions are prepared according
to known processes. As pharmaceutical compositions the new
compounds can be used as such or possibly in combination
with suitable pharmaceutical support substancesO If the new
pharmaceutical preparations contain pharmaceutical support
substances besides the active principles, the active prin-
ciple content of these mixtures is from 5 to 95, preferably
25 to 75, per cent by weight of the total mixture.
According to the Invention it is possible for -the
active principles to be used in human and veterinary
medicine in any desired form, for example systemic or
topical, pro~ided that one ensures the formation or main-
tenance of adequate blood or tissue levels or local
concentrations of 2-benzyi-perhydroazepins. This can be
done either by oral, rectal or parenteral administration
in suitable doses~ However, ~he new pharmaceutical com-
positions can also be applied locally. More advantageously
the pharmaceutical preparation of the acti~e principle
occurs in the form of unit doses, which are designed for
the particular administration desired. A unit dose may
consist, for example, of a tablet~ a pill, a capsule,
" .
'. :
'' ~
... , : :
... . . . .
:: ' :

- 17 ~
a suppository or R measured volwne of a po~der, a granula-te,
a solution, an emulsion1 a suspension, a sol or a ~el.
The term "unit doSe" within the meaning of the present
Invention i5 used to mean a physically determined unit
which contains an individual quantitiy of ths ac~i~e
component in combination with a pharmaceutical support,
the active principle content o~ which corresponds to a
fraction or a multiple of a therapeutical individual dose.
An individual dose preferably contains the quantity of
active principle which is dispensed in a single application
and ~hich usually corresponds to a whole, a half, a third
or a quarter of a dailydose. If for an individual thera-
peutical administration only a fraction, such as a half or
a quarter, of the unit dose is required, the unit dose
is advantageously divisible, for example in the form of
a tablet with a notch.
The pharmaceutical preparations according to the In-
vention, if they occur in unit doses and are intended for
application, for example, to man, contain 1 to 200 mg,
advantageously 2.5 to 100 mg, and especially 5 to 50 mg
of active pri~ciple.
In general it ha~ been found ad~antageous both in human
medicine and also in veterinary medicine to a~minister the
active principle or principles in the case of oral admini-
~ '"" ' ,
.
:' ' , . . .: ~ ' ' ' :

stration in a daily dose of Q .o6 to 12, preferably 0.1l~to 5.7, aspecially 0.3 to 3 mgJkg body weight, possibly
in the forrn of a number, prefarably 1 to 3, of individual
dos~s so as to achieve the desired re~ult~. An individual
administration contains the active principle or principles
in quantities of O.O1 to 3.0, preferably 0.04 to 1.5,
especially 0.07 to 0.7 mg/kg body weight.
In the case of a parenteral treatment, for example of an
acute depression or of a strong pain condition, similar
dosages can be used. In the case of this therapy, 1 to
50 mg of active principle are applied.
For a local application one can use preparations in a
pharma¢ologically acceptable, for example aqueous, solution,
which contain 0.1 to 5, preferably 0.2 to 3, especially
0.5 to 2 per cent by weight of acti~e principle.
The therapeutical administration of the pharmaceutical
preparations in the case of permanent medication is carried
out generally at fixed times, such as for example 1 to ~
times a day, for example after meals and/or in the evening.
In the case of acute attacks the medication is carried out
at ~arying points of time. Under certain circumstances it
may be necessary to differ from the dosages mentioned5
namely according to the nature, the body weight and the age
of the patient under treatment, the nature and severity
:'~
.' :
, . , , ' -
: . . . .. .
.: . .
: . : . ,
:. :
.

- 19 ~ 3~7'''~
of the disorder, the nature oC the preparation and tlle appli-
cation of the pharmaceutical product as well a~ the interval
~ithin which the administration takes place. Thus in a
few cases it may be ~ufficient to rnanage with less than
the quantity of acti~e principle mentioned above, whilst
in other cases the abovementioned quantity of active prin-
ciple will have to be exceeded. The determination of the
optimum dose and form of application of the active prin-
ciples necessary in each case can be carried out at any
time by the technician on the basis of his technical
knowledge.
The pharmaceutical preparations consist as a rule of
the active principles according to the In~ention and
non-toxic pharmaceutically compatible pharmaceutical
supports which are used as an admixture or diluent, in
a solid, semi-solid or liquid form or as an enrobing
agent, for e~amp}e in the form of a capsule, a tablet
. .
coating, a bag or another container, for the therapeutically
active component. A support material can, for example,
serve as a medium for ab30rption of the medicament by
the body, as a formulation aid, as a sweetener, as a
taste corrector, as a colouring material or as a preser-
vative.
.
.

_ 20 ~ 3'7~ ~
For oral application one c.~n use, for example, tablets,
pills, hard ancl soft capsules, for example of gelatin,
dispersible powdcr, granul~tes, ~queous and oily suspensions,
emul sions, solutions or .syrup s .
Tablets can contain inert cliluents, for ex:ample calcium
carbonate, calcium phosphate, sodium phosphate or lactose;
granulating and distributing agents, for example maize
starch or alginates; binders, for example starch, gelatin
or acacia ~;um; and lubricants, for example aluminu~n or
magnesium stearate, talcum or silicone oil. In adclition
they may be provided with a coating which can also b~ such
that it ensures a delayed dissolution and resorption of
the pharmaceutical produc t in the gas-trointestinal tract
and consequently, for example, an improved compatibillty,
protraction or retarding effect. Gelatin capsules can
contain the pharmaoeutical produc-t mixed with a solid
diluent, for example calcium carbonate or kaolin, or an
oily diluent, for example olive oil, groundnut oil or :
1 i qui d paraff in~
Aqueous suspensions can contain suspending agents, for
example sodium carboxymethylcellulose, methylcellulose,
hydroxypropylcellulose, sodium alginate, polyvin~lpyrroli-
done, gum dra~;on or acacia gum; dispersants and wetting
a~;ents, for example polyoxyethylene stearate, heptadeca-
~' ' .
, , . , . -
.,. . .... ,
: ' - ,'- ' : :
: ~ .: ,
:. ' - : '

- 21 ~
ethylene oxycetanol, polyo~yethylene sorbitol monooleate,
polyoxyethylene sorbitan monooleate or lecithin; preser-
vatives, for exarnple methyl or propyl hydroxybenzoates;
flavouringY; sweeteners, for example saccharose, lactose,
sodium cyclamate, dextrose, invert sugar syrup.
Oily ~uspensions may contain, for example, groundnut
oil, olive oil, sesame oil, coconut oil or liquid paraffin
and *hickeners, such as for example beeswax, hard paraffin
wax or cetyl alcohol; they may also contain sweeteners,
flavourings and anti-oxidants.
Powders and granu}ates which are dispersible in water
may contain the pharmaceutical products mi~ed with dis-
persing, we-tting and suspending agents, for example with
those mentioned above, as well as with sweeteners, P~a-
~ouring~ and colouring materials.
Emulsions may contain, for e~ample, olive oil, groundnut
oil or liquid paraffin as well as emulsifiers, such as for
example acacia gum, gum dragon, phosphatides, sorbitan
monooleate, polyoxyethylene sorbitan monooleate, and
sweeteners and flavourings.
For rectal adm~.nistration of the pharmaceutical compo-
sitions one uses suppositories which are produced with the
aid of binders which melt at rectal temperature, for example
cocoa butter or p~lyethyl~neglycols.
' -'''
~' .
.. : ' . ' , : :
':

- 22 ~
For the parellteral applicatioll of the pharmaceutical
composi-tions one uses aqueous suspensions for ~terile
injection, isotonic saline solutions or other solutions
which can contain dispersants or wetting a~ents and~or
pharmacologically compatible diluents, for example propy-
leneglycol or butyleneglycol.
Gels, s015 or tablets which are suitable fo~ local
treatment may contain in addition to the active principle
or principles the usual supports, for example animal and
vesetable fats, waxes, paraffins, starch, gum dragon,
cellulose derivatives1 polyethyleneglycols, silicones,
bentonites, silica, talcum and zinc oxide or mixtures
of these substances.
Powders and sprays may contain, in addition to the
: active principle or principles, the usual supports such as
for example lactose, talcum, silica, aluminium hydroxide,
calcium silicate and polyamide powder or mixtures of
these substances. In addition, sprays may contain the
usual propellants, for example chlorofluorinated hydro-
carbons.
If desired, the active principles can also occur in
a microencapsulated form with one or more of the above-
mentioned support materials.
''
~: .
, ' ~ .
,

23 ~ 3t~
In addition to the 2-benzyl-perhydroazepine~, the
pharmaceutical preparations may contai:n for example one
or more pharmacologically active compo:nents belonging to
other groups of pharmace~tical products, for example
: mild stimulants, such as caffein; analgesic~,such as amino-
phenazone, acetylsalicylic acid, d-propoxyphene; anti-
depressives, Debenzepin, Doxepin, Maprotiline, Amitriptyline,
~ Nortriptyline, Melitracene; tranquilisers, such as benzo-
diazepines, e.g. Diazepam, Chlordiazepoxide, Meprobamate,
substances for promoting cerebral circulation and/o:r
roborifacients, such as glutamic acid, vitamins or combina-
tions thereof.
This invention also provides a method for the
treatment of mammals lrhich are suffering from primary or
secondary disorders of the central nervous system from
pain, or from pathological variations in the blood pressure,
~hich is characterised by the fact that the mammal in :~
question is given a C~S- or analgesic effective or a blood
pressure-regulating and pharmacologically compatible
quantity of one or more 2-benzylpyrrolidines and/or their
pharmacolog.ically toLerated salts.
The intermedia~..e products ~f the general formula I.or
of the embodiments I~ or I~ can be converted by known ~.
:.. --- - - -. .

- 2l~ -
methods into pharmacologically effecti~e compounds of the
general formula I, as set out in the followin~ Examples.
Thus, inter alia, one obtains from the free bases the
acid addition salts by reaction with the corresponding
acid. Ethers, that is to say those compounds in which one
or more of the substituents R2, R3, R4, R5 represent an
alkoxy group or two neighbouring substituents R2, R3,R ,
R5 jointly represent an alkylidenedioxy sroup, are conver-
ted by acid hydrolysis, for example with hydrogen halide,
into the free hydroxy compounds. ~sters, that is to say
those compounds in which one or more of the substituents
R2, R3, R , ~5 represent an acyloxy group, are converted
by alkaline hydrolysis, for example with sodium hydroxide,
into the free hydroxy compounds~ The free hydroxy compounds,
that is to s~y those in which one or more of the substituents
R2, R3, R4, R5 signify an OH group, can be etherified or
esterified.

- 25 -
Furthermore, thi~ invention provides a process for the
production of 2-ben7.yl-p~rhydroazepines of the Seneral
formula I and its embodiments I* or I**, which is
- characterised by the fact that
A) a 2-benzyl-azacycloheptane of the general formul~
X ~ \ ~ ~ (II~,
E?
in which R2, R3, R aIld R5 have the meanings given above
and :
X Z- ~ignif~es on~ of the grouping~ N ~ CH2-,
' N ~ CH-, O ~ C~ and ~ ~ C
.-- (b) (c) (d)
R signifies an aliphatic or alicyclic hydrocarbon radi
cal, a cycloalkylalkyl group or an aralkyl group and
R signi~ies a hydrogen atom, an aliphatic or alicyclic
hydrocarbon radical or a cycloalkylalkyl radical, is
reduced and if desired then N-alkylated or N-de-alkyla-
ted and/or functionalised and/or the free base obtained
or its acid addition salts are converted into one another
.,
.:
. ~
"'~" ' ' - '' : ' ' ., :. ' ,
-:, . , , ~ . ~ :
. . .
.. , . , ::

in the usual Inanner or
B) a 2-benzyl-azacycloheptane of the general formula III
. ,
'' ' A ' ''
~ N 1 CH2 ~ (III~,
., . I
: R7
in which R7 has the meaning given above and G signifies
a hydrogen atom or a precursor of a functional group
and n is a whole number from 1 to 4, preferably 1 to 2,
especially 1, is functionalised and if desired is then
N-alkylated or N-de-alkylated and/or the free base ob-
tained or its acid addition salts are con~erted into
one another or
C) a N-acyl-2-benzyl-azac~cloheptane of the general formula .
IV
~2
~rl 1CH {~ (IV~,
CO_R8 5
:: . '
.,
~ ,.,,. . - . , :
. ::, . - - .. :, ... , . :
:
: .
. . .

- 27 -
in ~hich ~2, R3, I~ and R5 have -the meaninss gi~en above
and n sisnifies an aliphatic or ~licyclic llydrocarbon
radical, a cycloalkylalkyl radical, an optionally
substituted phenyl radical or phenalkyl radical, is
reduced and if desired is then functionalised and!or
N-de-alkylated and/or the base obtained or its acid
addition salts are converted into one anoth~r in the
usual manner.
The reduction of the substituted 2-ben~yl-azacyclo-
hQptanes of the general formula II is preferably carried
out with hydrogen in organic solvents, such as is current
to the technieian dealing with hydrosenation reactions,
for example ethanol, methanol, cyclohexane, isopropanol,
dimethylfarmami'de, in the presence of metallic catalysts,
for example platinum7 platinum on active carbon, palladium,
palladium on acti~e carbon, Raney nickel, under pressures
of 1 to 500 atmospheres and at temperatures around room
temperature, for example 0 to 50Co The reduction of the
compounds of the formula IIa and IIb is alternati~ely
carried out in the form of their aeid addition salts in
aqueous alcoholic solutio~ with sodium borohydride in the
manner usual for the technician (cf. "Enamines: Synthesis,
Structure and Reactions~ edited by A. Gilbert Cook pages
185 et seqq.; 3~1ARCEL DEKKER, New York and London 1969).
'
~;
:,,
:- . . ~ ,. - . . . - .

28 ~ '7'~
The reduction of the compounds IIc is effected with
lithium aluminium hydride in inert solvents, such as ethers,
e.g. diethyl ether, tetrahydro~uran, dio~an, 1,2-dimethoxy-
ethane or diethyleneglycol diethyl ether, at temperatures
between 0 C and the boiling temperature of the solvent,
preferably between 20 C and 70C. The reduction of the
compounds IId is effected alternatively by reaction
~rith hydrogen halides, preferably hydrogen chloride, in
inert solvents, e.g. benzene, in analogy to the process
described in Synthesis 1976, 540-41.
The compounds of the general formula IIa to be used as
initial compounds
Q CN~ ~ ~IIa)
'
in which R2, R3, R and R5 have the meanings given above,
are obtained for example by reacting 2-benzylideneaza-
cycloheptanes of the general formula V
. .
,:
:

- 29 -
CN ~ R4
in which ~2, R3, R and R5 have the meaninss given above,
~ith strong mineral acids. The hydrolysis and simultaneous
decarboxylation of the nitril~s V is carried out ~ith
mineral acids such as hydrochloric acid, hydrobromic acid,
sulphuric acid, preferably concentrated hydrochloric acid,
at temperatures between room temperature and 120C, pre-
ferab}y by heating the relevant solution under a reflux
until the evolution of carbon dioxide ceases. The resultant
imines IIa are relati~ely unstable compounds so that it
is wise to process them further straight away, that is
to say hydro~enate them to form the perhydroazepins.
The benzylidene compounds V are obtained for e~ample on
th~ basis of the process described by T~ Kameta~i a~d
others ~J.Chem.Soc.,Perkin I 1976, 389; Heterocycles 3
[1975] 691). In this a caprolactim ether, preferably
caprolactit~methyl ether, is reacted ~ith a corresponding
arylacetonitrile, for e~ample 4-chloroph~nylacetonitrile,
.. ., . ~ . ~ . . . .
, :. . . : :; ; . . : .:
. ~ .

'7~
- 30 -
in the prescnce of ~n au~iliary base, such as diazabi-
cycloundecene, diazabicyclononene, triethylamil1e, ethyl-
diisopropyl~mine, either without solvent or in the presence
of an inert solvent such as benzene, toluene, xylene,
cyclohexane, at temperatures of 50 to 150 C, prcferably
100 to 130 C, and optionally under an i.nert gas, for example
nitrogen. It is p.referable to carry out the reaction ~ith-
out using an inert solvent.
The initial compounds IIb can be prepared accord.ing to
various processes. For example they can be obtained by
reacting N-substi-tuted caprolactam derivatives VI ~ith
phenyl~cetic acid derivatives VII to ~orm the benzylidene
compounds VIII, their hydrolysis and decarbo~ylation
according to the following reaction scheme
~2 3 R2
N / = 0-R R ~ R ~ \~ f ~n3
(VI) tVII) (VIII)
~III ~ IIb
'
:
'~
' ,' , : ' . ' ' ;'
': ', ' ,, , ~ f.
.'' ': ~

- 31 -
in which
R2, R3, R , R5 and R have the meaninss given above
and R13
R9 sisnifies a -0-R12 sroup or a -N < 14 ~roup,
R11 si~nifies a -CN or -Co-o-Ri5 group,
R , R , R 3, R and R 5 are the same or different and
signify an alkyl radical ~ith l to 5 carbon atoms,
preferably a methyl or ethyl sroup, and
R14 also signifies a phenyl radical, or else R9 and
~0-R jointly represent an alkylidenedioxy group with
up to 4, preferably 2, carbon atom~.
The reaction of the caprolactam deri~tive VI with the
phenylacetic acid derivatives VII is generally carried
out at temperatures of 20 to 150C, preferably between
40 and 100 C, without or preferably with the addition
of inert organic solvents such as aliphatic
hydrocarbons, for example petrol ether, light petrol,
ligroin, or else cycloaliphatic hydrocarbons such as
for example cyclohexane, or aromatic hydrocarbons, for
example benzene, toluene, xylene. The hydrolysis and
simultaneous decarboxylation of the benzylidene derivatives
VIII ~esters or acetonitriles) is carried out by the action
of mineral acids, such as hydrochloric acid, hydrobrotnic
acid, preferably concentrated hydrochloric acid, at
, ' ' .; , ' ! .
: ' ' . . , , ' . ' ., , , ' ' ':
', ' . ' ~ , ' :, ., , . . :
'. ' ' ' ' ' ., ' ' ' ' : ' ' , . '
'''"',' ~, . ~ : ' , ' ~

- 32 -
::
temperatures bet~een room temperature and 120C, preferably
by heatins the corresponding solution ~Inder a rcflu~
until the e~olution of C02 ceases. The enamines IIb
resulting from the esters VIII or the correspondins
acetonitriles are relatively unstable compounds and are
senerally further processed immediately, that is to say
hydrosenated to form the compounds accordins to the
Invention. Because of their stability and their easy
accessibility and also because of the instability of the
enamines IIb the esters VIII or the correspondins aceto-
nitriles constitute interesting and valuable intermediate
products for the production of the 2-benzylperhydroazepins
I according to the Invention.
The N-substituted caprolactam derivati~es VI are knol~n
.,
.
compounds or are obtained by known processes.
The acid amideacetals ~I (R9: -0-R12) are obtained
for e~ample by reacting N-alkyl-caprolactam with alkylating
asents such as dimethylsulphate, diethylsulphate, alkyl
p-toluenesulphonates, to form the salts IX (R9: ~0-R 2)
and their subsequent reaction with alkali metal alcoholates,
such as sodium methylate or ethylate. Aminal esters VI
(R9: -NR13R14) are obtained by reacti~g the salts IX
~R9: -~R13R14) with alkali metal alcoholates, such as sodiw
methylate or ethylate, in inert sol~ents such as benzene
,
:
.'
, ,. : , '
.

- 33 -
ethers, for e~alnple diethyl ether.
The initial compounds IIb) are obtained according to
a further process by reacting azepinium salts IX with phenyl-
acetic acid derivatives VII in the presence of strong
bases to form the benzylidene compounds VIII and their
hydrolysis and decarbo~ylation in~accordance ~ith the
followin~ equation
9 L~ + VII )VIII~ IIb
16 :
IX
in which R6 and R9 have the meanings ~iven above, and
L~ signifies an equivalent of an anion of an organic or
~ inorsanic acid.
The reaction of the azepinium salts IX with the phenyl-
acetic acid derivatives VII usually takes place without
the addition of further solvent in the presence of strong
basss, such as solutions of alkali metal alcoholates,
for e~ample sodium methylate, potassium msthylate, pOtaSsiUm
propylate, sodium isopropylate, potassium butylate,
' ` ~
'~:
: ::: ., .. : : . .. .
: ~ . ' . ', : ' . ; '
:
, ~
. . . , ~

_ 3~ _
pOtassium tert.-butylate, potassium tert-pentylate,
especially sodium ethylate, at ten~peratures of 20 to 150 C,
preferably 80 to 100 C. If desired the reaction is carried
out whilst passing through an inert gas, such as nitrogen,
in order to remove any ~olatile amine which is formed.
However, the reaction can also be carried out with the
addition of inert solvents~ such as alcohols, for example
methanol, ethanol, propanol, isopropanol, bu-tanols, pen-
tanols; tertiary nitrogen bases, for e~ample pyridine;
or hydrocarbons, for example benzene. The hydrolysis and
decarboxylation of the benzylidene compounds VIII is
carried out analosously to the proces~es described above.
The production of the salts IX, of which those with
R9 in the meaning of a -NR 3R ~ group are preferred, is
carried out for example in analogy to ~I.Bredereck and others
(Chem.Ber. 1964, 3081) by the reaction of the corresponding
N-substituted caprolactams with alkylatins agents, such
a~ diethylsulphate, methyliodide and preferably dimethyl-
sulphate, in inert solvents at room temperature up to
120C, preferably ~Yithout solvents at temperatures around
80C and, if in t~le salts IX R9 represents a -N~13R 4
group, subsequent reaction with the amines I~R13Ri4 or
also by reacting the corresponding caprolactams with
inorganic acid chlorides, such as phosphorus oxide chloride,
:, .
.
,

- 35
phosgcne follo~ed by reac-tion with the amines EIN~ 3R 4
in inert solvents, such as ben~ene, at temperatures bet-
~een 0 and 100 C, preferably between 20 and 60 C, or
without solvents at temperatures between 0 and 100Ç,
preferably between l~o and ~0 C.
The initial compounds IIc are obtained according to
methods known in the art. Starting compounds IIc ~herein
R signifies a hydrogen atom are obtained, e.g. by rearrange-
ment of the corresponding 2-benzylcyclohe~anones accordingto
the process described by T. Duong et al. [Austr.J.Chem. 29
(1976) 2667-o2, particularly page 2681]. They are also
obtained by functionalisation of 7-benzylhe~ahydroazepin-
2-one accordins to methods described in the follo~ing para-
graphs. Starting materials IIc whorein R signifies an
aliphatic or alicyclic hydrocarbon radical, a cycloalkyl-
alkyl group or an arallcyl group are obtained by N-alkylation
of the corresponding 7-benzyl-hexahydroazepin-2-ones.
A con~enient method9 e.g. is described by T. Duong et alO
LAustr.J.Chem. 29 (1976) 2651~65, particularly page Z660].
The initial compounds IId are obtained for example by
lithiation of 1-nltrosoperhydroazepin and subsequent -
reaction with corresponding ben~yl halides, preferably
bromides or iodides, in accordance with the process des-
cribed in Synthesis 1976, 540-~1.
'''

~ 36 -
The functlonalisation of the 2-benzylperhydroazepins
III or the optional subsequent functionalisation of the
:` 2-benzylperhydroazepins I obtained by reduction or of the
starting materials IIc are carried out according to the
nature of the substituents ultima-tely desired in the
phenyl group.
The nitro group is int~oduc~d ~or example by nitration
~ith ni-tric acid, nitric acid/sulphuric acid, potassium
- nitrate/sulphuric acid, alkyl nitrate at temperatures
from -20 to +50C, preferably -20 to +30C. In the initial
compounds, e.g. III, G then signifies a hydrogen atom and
n =1, and in the end products R2, R4 and R5 ha~e the
meaning of a hydrogen atom and R3 has the ~neaninS of an
N02 group in the para position. Under more severe conditions
dinitro compounds are obtainèd, that is to say R4 and R5
have the meaning of a hydrogen atom and R2 and R3 that of
a nitro group.
The amino group is introduced by the reduction of the
N02 group or groups of a corresponding nitro compound
with hydrogen over suitable catalysts, such.as Pt; Pt/C,
Pd, Pd/C, Raney nickel in the usual solvents, such as
alcohols, cyclohe.Yiane. In the initial compounds III, G
then means one or two N02 groups and n = 1 (or 2), and
: in the end products R4, R5 have the meaning of a hydrogen
. , ~ , . . .
::

- 37 ~
atom and R2 and/or R3 that of an NH2 group.
Halogen atoms, especially chlorine and bromine atoms,
are introduced in the usual manner by halogenation of the
rinS. For the halogenation of the ring one uses as cata-
lysts iron, ferric chloride or bromide, aluminum chloride
or bromide, tin tetrachloride or iodine, the reaction
being carried out ~ithout or in inert solvents, if desired
also in glacial acetic acid without a catalyst at tempera-
tures between 0 and 20 C.
Hydroxy groups are introduced by ether splitting of
the corresponding alkoxy groups. In the initial compounds
III, G then signifies an alkoxy group, preferably a
methoxy group, and n = 1 to 4, preferably 2, especially
1~ The ether splitting is carried out, for example, by boi-
ling with hydriodic acid or hydrobromic acid or mi~tures
of hydrobromic acid/glacial acetic acid or by reaction
with boron tribromide in inert solvents, such as chloro-
~form, dichloromethane, at temperatures of from -20 to 20 C.
The etherification is carried out for e~ample by
reacting correspondins hydro~y compounds (G in the initial
compounds III then means a hydro~y ~roup; n = 1 to 4,
preferably 2, especially 1) with alkyl halides in the
presence of equivalent quantities of alkali metal alcoholate,
for example sodium ethylate.
. .
:. ~''~;' , ' , -
:. .

- 38 ~
. .
The functionalisation of ~r~e I~yclroxy groups or amino
gro~lps in thc form of acyla-tion or a possibly successive
acylation is carried out accordins to ~ethods kno~n to
the technician, for e~ample by reaction with the correspon-
ding acid anhydrides or halides (cf. inter alia Houben Weyl,
Vol. o, pages 543 et seqq. or 655 et seqq.) The splitting
off of the acyl groups with the liberation of hydroxy
groups or amino groups is carried out in the usual manner
by saponifica-tion, for example by reac-tion with suitable
bases, such as caustic soda or potash.
The N-alkylation, in ~rhich alkyl also includes the
meaning of cycloalkyl, arallcyl and cycloalkylalkyl, is
carried out by methods Icnot~n to the technician. Thus the
N-alkylation is carried out with alkylating agents, such
as alkyl halides, alkyl sulphonates, for example tosylates,
alkylsulphates, in inert solvents such as acetone, methyl-
ethylketone, alcohols, such as methanol, ethanol, iso-
propanol, dimethylformamide or without solvents, using an
auxiliary base, such as sodium carbonate, potassium
carbonate, triethylamine, at -temperatures from 20 to 100C.
The N-de-alkylation, in ~hich alkyl also includes the
; meaning of cycloalkyl, cycloalkylalkyl and aralkyl,
especially benzyl, is carried out according to kno-m methods.
The N-de-alkylation is carried out for example with
.,
~ .
'; - . : ~ -
:- ~ . . '., ~ :
:: :: . . :

3~
chloroformate esters, such as ethyl chloroformate, a ,~,
~,-trichloroethyl chloroformate, without or in the presence
of inert sol~ents such as benzene, toluLene, chloroform,
at elevated temperature, preferably at the boiling point
of the solvent. The intermediate product obtained is
reacted with aqueous or alcoholic solutions of bases,
such as caustic soda/ethanol, caustic potash/butanol,
at elevated temperature, preferably at the boiling point
of the solvent, to form the corresponding de-alkylperhydro-
azepin, that is to say to form the compound of the general
formula I in which Rl signifies a hydrogen atom.
The N-de-alkylation in the special form of de-ben~yla-
tion, that is to say when using compounds of the formula I
in which Rl = benzyl, is carried out by the hydrogenolysis
in the presence of catalysts, preferably palladium on
carbon, in solvents such as methanol, ethanol, benzene,
; cyclohe~ane, at O to 50C, preferably room temperature,
and a hydrogen pressure of 1 to 300 atmospheres, preferably
1 to 5 atmospheres.
Acid addition salts are obtained by dissolvin~ the free
base in a suitable solvent, for example acetone, water,
a low-molecular aliphatic alcohol (ethanol, isopropanol)
or ether (diethyl ether, tetrahydrofuran) which contains
the desired acid, o~ to which the deslred acid is afterwards
:
.,: .

- ~tO ~
~,
added. The salts are recovered by filtration, precipita-
tion with a non-solvent of the addition salt or by eva-
porating off the solvent.
'!" The salts obtained, for example the hydrochlvrides,
can be converted into the free base by neutralisation
with aqueous sodium or potassium hydroxide, and the base
can then be recovered by solvent extraction using a
suitable solvent which is not miscible with water, such
as chloroform, dichloromethane, ether, benzene, toluene
or cyclohexane. The free bases can also be obtained by
neutralisation of an acid addition salt with sodium
methylate in methanol and isolation of the base using
known processes. Salts can also be converted into other
salts, for example pharmacologically compatible acid
addition salts, by conversion into the base followed
hy further reaction with an acid.
Any racemate splitting whiGh may be necessary or desired
is carried out in the usual manner, for example by mixinS
~ith an optically acti~e acid, such as mandelic acid,
tartaric acid, camphorsulphonic acid or dibenzoyltartaric
acid, the recrys~llisation o~ the resultant salt until
the refractive index is constant and liberating the opti-
cally active base with alkalis. From the mother liquors
occuring during the recrystallisa-tion one obtains the other
~ .
',; ~
~..
~ . ' '. .

enantiomer in an anc~logous fashion.
The reduction of the N-acyl-2-ben~yl-a~acycloheptanes
of the general formula IV is carried out according to
known methods, for example by reaction with a complex
metallic hydride as reducin~ a~ent in an anhydrous organic
solvent and hydrolytic working up. Suitable reducins agents
include lithium aluminium hydride (lithium hydridoaluminate) ;~
as well as sodium dihydrido-bis-(2-methoxyethoxy~-aluminate.
As solvents one may use inert anhydrous ethers, suc:h as
diethylether, tetrahydrofuran, dioxan, 1,2-dimethoxy-
ethane and diethyleneglycoldiethylether, as well as
aromatic hydrocarbons, such as benzene and toluene, or
mixtures of the said compounds. The temperature of the
reaction is not critical and can vary within wide limits,
for example from O to 100 C. As a rule it is best to carry
out the reaction at the reflux temperature of the reaction
mixture~ The duration of the reaction depends upon the
reaction temperature used ~nd may vary between 1 hour and
24 hours. At the preferred reflux temperature the reaction
normally ends in 3 to 4 hours. The reactants can be used
in equivalent quantities, but an excess of the reducing
agent is preferred. After the reaction with the reactant
the reaction product is then processed by treating the
reaction mixture with an aqueous medium such as water,
.
.
~ . .
~ . '
: . .-
.: ; ' ' ':
, ~

_ 42 -
dilute aqueous inor~anic acids or basec or other media
containing water. The product can be isolated as the free
base or as acid addition salts by adju~ting the pH.
The starting compounds of the general formula III are
obtained for example by de-methylation of 2 benzyl-1-
methylperhydroazepin (to III wherein R1: -H) and optionally
subsequent N-allsylation (to III wherein R1: allcyl, cyclo- :
alkyl, aralkyl, cycloalkyl.alkyl).
: The production of the initial compounds of the formula
IV is also carried out by methods which are known to the
technician, for example by the acylation of the corres-
ponding 2-benzylperhydroazepins I (R~ I) with carbo~ylic
acid halides, such as Cl-CO-R~ 7 in which R$ ~Ias the
meanin~ given above, or carboxylic acid anhydridas in inert
; solvents, such as benzene, toluene, cyclohexane, chlorofor~,
dichloromethane, in the presence of an a~xiliary base,
-~ such as pyridine or triethylamine, at temperatures between
O and 50 C. Suitable carboxylic acid halides, for example,
. are acetyl chloride, propionyl chloride, bu-tyryl chloride,
: pivaloyl chloride, cyclopropylcarbonyl chloride, cyclo-
butylcarbonyl chloride, benzoyl chloride, phenylacetyl
chloride.
':~
, - : , , . ~:

:~ ;
'rlle follo~ring e~ nples e.~plain tllc Invcntion i.n greater
det~ rithout restricting it. The abbreviation ~IP signi-
fies meltin~ point, BP signifies boiling point, dec.
si~nifies decomposition. The temperatures are given in C.
~.
' ~ :
. . .
: . .
,. I
~,
. ~ - . . : ~- . -
- -: :: ; .:
'' ,:' . ' . ~ :
.. . ... .
.. . . . :
. ~:
:.
.

~.4IPL~S
Exam~le
2-dimcthylatnino-1-methyl~ ,5,6 ! 7-tetraI~ U~
nethylsulph?te
190 g of N-methylcaprolactam and 189 g of dimethyl-
sulphate are stirred for 3 hours at oO C, after cooling
they are shaken ~ith ether and then freed from solvent
residues in vacuo. The light yellow oil so obtained
(3l~6 g) of 2-metho~y-1-methyl-4,5,6,7-tetrahydro-3H-azepinium
methylsulphate is added drop by drop to a solution of
110 g of dimethylamine in 600 mls of benzene ~hilst
stirring and is boiled under a refl~x for 90 minutes.
The heavy phase is collected and extracted several times
with etherO The yello~ h oil is concentrated in vacuo.
~::
Yield 336 g (93 % of theory),
E~ample 2
2- ~-(ethoxycarbonyl)-l~-c~lorobenzylidene~ methylperhydro-
azepin
To a mixture of 53.2 g of 2-dimethylamino-1-methyl-
/~,5,6,7-tetrahydro-3II-azepiniun~ methylsulphate and 29.~ g
of ethyl ~-chlorophenylacetate one adds drop b~ drop at
90 in a stream of nitrogen a solution of ~.6 g of sodium
.
,
-, , -:

_ l}5 ~ 3''~
in lOO mls of etl1yl alcohol. l~hen tl1is is done the ~lcohol
is rcmo~ed from the reaction Inixturc. It is stirred for
a further 4 hours at ~0 , the cooled mix-ture is mixed
~ith lOO mls of water and 100 mls of ether, the organic
phase is collected and dried over sodium sulphate. Any
excess ethyl 4-chlorophenylacetate is remo~ed after con~
cen-tration by distilling off in high vacuum. Crude yield
15.5 ~ (34 % of theory), yellow oil.
Example 3
. .
2-r~-(ethoxycarbonyl~-3,4-dimethoxybenzylidene~ me-thyl-
perhydroaz~pin
According to the method described in Example 2, one
obtains from 53.2 g of 2-dimethylamino-l-methyl-4,5,6,7-
tetrahydro-3H-azepinium methylsulphate, 33.6 g of ethyl
3,4-dimethoxyphenylacetate and a solution of 4.6 S of
sodium in 100 mls of ethyl alcohol the title compound
`~ as a viscous yellou oil with a BP of 175 to 180 (O.OOl mm Mg).
Yield o.6 g (17 S~ of theory)O
Example 4
:
2-r~C-(ethoxycarbonyl)-4-me-thoxybenzylidene]-l-methylper-
hydroazepin
Using thc method described in ~xample 2 one obtains
.~ , .
~. '.

- I~6 ~ t~'f~
from 53.2 S f 2-dimethylamino~1-me-thyl-4~5~6,7 tetra-
l~ydro-3II-azepiniIlm methylsulphate, 29.1 g of ethyl l~-
methoxyphenylacetate and a solution of 4.6 g in lO0 mls
of ethanol, the title compound as a viscous yellow oil
with a BP of 165 (O.OOl mm Hg). Yield 15.6 g (34 % of
theory).
E~ample 5
2- L4(-(ethoxvcarbonyl)-3-methoxybenzylidenel-l-methy~ ~ .
hydroazepin
Using the mode of operation described in Example 2
one obtains from 74.9 g of 2-dimethylamino-l-methyl-1~,5,
6,7-tetrahydro-3H-azepinium methylsulphate, 40 g of ethyl
3-metho~yphenylacetate and a solution of 6.4 g of sodium
in 160 mls of ethanol, the title compound as a viscous
oil. Yield 3~.6 g (62 ~0 of theory).
Example 6
2-(4-chlorobenzyl)-l-methylperhydroazepin
15.5 g of 2-C~-(ethoxycarbonyl)-4-chlorobenzylidene]-
l-methylperhydroazepin and llO mls of concentrated hydro-
chloric acid are boiled under a refl~ until the evolution
f C2 ceases, after cooling it is alkalised ~ith caustic
soda solution, ~hilst cooling ~ith ice, and extracted ~ith
.
- : , , .

ether. The ether phase is concentrated and driccl over
sodi~n sulphatc. The rosidual 2~ -chlorobcnzylid~ne)-1-
methylperhydroazepin (7.~ S) is dissolved in ethyl alco-
hol and hydrogenated with platinum/active carbon/hydrogen.
The product, after filtering off the catalyst and distil-
lins off the solvent is distilled in high vacuum. Yield
4.4 g with a BP of 102 to 110 at 0~003 mm lIg.
The picrate (from ethyl alcohol) melts at 120-121 .
The reaction of the base with the equivalent quantity
of the corresponding acid gives the following salts:
Hibenzate: colourless oll
Citrate: colourless oil
Futnarate: light ycllo~ oil
Benzoate: light yellow oil
~Ialeate: light yellow oil
~mbonate: yellow oil
;~ , .
Example 7
2-(3,l~-dimethoxybenzyl)-1-methyl-perhydro~
.~
Using the mode Or operation de~cribed in ~xample 6
one obtains from '12.28 g 2-r~-(ethoxycarbonyl3-3,4-dimethoxy-
benzylidene~-1-methylperhydroazepin the title compound
with a BP of 117 at 0.001 mm I-I~.
The picrate (~rom ethyl alcohol) melts at 127-129 .
~ .
.
.
'

:
~ ,p
2-[(~-cyano)-benzylidene~ perhydroaY~T)i!~
~ .1 g of caprolactimmetllylet}ler, 5,0 S f benzyl
cyanide and o.6 g of 1,5-diazabicyclo[5.4.0]undec-5-ene
are agitated under nitrogen for ~S hours at 130 ; any
e~cess benzyl cyanide is distilled off in high vacuum and
the residue is ru~bed down ~ith a little methyl alcohol
an~ riltered off. In this ~ay onc obtains the title com-
pound (3.7~ g), ~1ich is recrystallised from met11yl alco-
hol for further purification. ~IP 10~-113.
~ampl _
2-[(~-cyano~-4-chlorobcnzylidene~-perllvd oazepin
5.0 g of 4-chlorobenzyl cyal1ide, 5.5 g of caprolac-tim
methyl ether and 0.5 g of diazabicycloC50l~.0]undec-5-ene
are agitated under nitrogen for 18 hours at 125 . After
cooling, the crystallising residue is rubbed do~n ~ith
20 mls of mcthyl alcohol and filtered. In -this way one
obtains the title compound (5.5 g), ~hich is recrystallised
from methyl alcohol. MP 111~-117 .
. ~
Example 10
2~ -chlorobenzyl)-~erhydro~zepin
100 g of 2-r(~-cyano)-4-chlorobenzylidene]-perhydroazepin
.~
, : ''
,: :
' '' . ~
: ................ , - ' ~
-

and 1 litre of concentratad hydrochloric acid are
boiled under a reflux until the evolution of carbon dioxide
ceases, after cooling it is alkalised with caustic soda
solution whilst cooling with ice and the~ extracted with
ether. After drying over sodium sulpha-te, the ether extract
is concentrated. The 2-'(4-chloroben2yl)-4,5,6,7-tetra-
hydro~3H-azepin so obtained
a) is hydrogenated with platinum/active carbon/hydrogen,
filtered off from the catalystl concentrated and distilled.
One obtains 61.9 g (68 %) with a BP of 93 at O.i mm Hg;
or
b) i~ di~ol~ed in diluted hydrochloric acid (pH~ 5) and
mixed with 200 mls of methyl alcohol~ 7 g o~ sodium
borohydride are added in small parts within 20 minutes 9
the pH-~alue i9 kept constant by occasional addition
of hydrochloric acid. lt is ~tirred for 1 hour, ren-
dered alkaline with caustic soda ~olution and extracted
with dichloromethane. The organic pha~e i~ dried over
~odium ~ulphate, concentrated and distilled. One obtai~
58 g with a BP of 93 at O.1 mm Hg.
The hydrochloride (from methyl alcohol/ether) melts at
177-178.
... . ~
,
.

~ 50
2-benzylperhydro~ze ~n
Usin$ the mode of operation described in Example 10,
one obtains ~rom 15 S of 2-~(~ cyano)-benz~lidene]-per-
hydroazepin and 177 mls of concentrat~d hydrochlori.c
acid 7~46 g (56 /O o~ theory) o~ the title compound with
a BP of 88 a-t 0.007 mm Hg~
The hydrochloride (from methyl alcohol/ether) melts
at 164-167,
Example 12
1-ethyl-2-(4-chlorobenzyl)~perhydroazepin
4 g of 2-(~-chlorobenzyl)-perhydroazepin, 2.5 g of
anhydrous potas~ium carbonate and 2.9 g of e$hyl bromide
are boiled under a reflux ~or 26 hours in 30 mls of
ethylmethylketone whil~t agitating, after cooling it i~
mixed with water and extracted with ether. The organic
phase iq dried over sodium su~phate, the ether i~ wi-th-
drawn and the residue distilled. One obtains 5.12 g
(70 %) with a BP o~ 112 at 0.005 mm Hg.
. ~
` U~ing the mode of operation described in Example 12
., : .
- . . . ., ~ .
:
. .
;,
,' ' ~ ` :

- 51
one obtai~s from 8 g of 2-(4-chlorobenzyl)-perhydroazepin~
5 g of anhydrous potas~ium carbonate a:nd 8.7 g of allyl
bromide, 6.76 g ~72 % of theory) of the title compound
with a BP of 110 at 0.02 mm Hg.
2-(4-chlorobenzyl)-1-isopropylperhydroazepin
Using the mode of operation de~cribed in Example 12
one obtains from 5.8 g of 2-(4-chlorobenzyl)-perhydroazepin,
3.6 g of anhydrous potassium carbonate and 6~6 g of iso- : .
propyl iodide 3.9 g of the title compound with a BP of
113 at 0.03 mm Hg (56 % of theory).
' .
Exam~le 15
. . .
2-(4-chlorobenzyl)~1 hexylperhydroazepin
Using the mode of operation described in Example 12
;one obtains from 5 g of 2-~4-chlorobenzyl)-perhydroazepin,
: 3.1 g of anhydrous potassium carbonate and 4 g of 1-bromo-
hexane, 3.87 g (56 % of theory) of the title compound ~ith
a BP o~ 129 at 0.005 mm Hg.
2-~ C ~
To 43 ~ls of concentrated sulphuric acid one adds drop
: .
:~
. ,. ~
~ ' ' ' '' ~

3~
- 52
by-drop whilst stirring at -10 10 g of 2-banzylperhydro~
azepin, then at *he same temperature one adds 33 mls
of concentrated nitric acid, it is allowed to heat 910wly
to room temperature and stirred for a further hour. One
pours i* into 500 g o~ ice, alkalises it with 6 N caustic
soda solution and extracts it with ether. After drying the
organic phase o~er sodium sulphats the solvent is distilled
of~. There remain 12.0 g (97 ~0 of theory) of the title
compound as a red oil.
Exam~le 17
2-(4-aminobenzyl)-perhydroazepin
12 g of 2-~4-nitrobenzyl)-perhydroazepin are hydro-
genated in 300 mls of ethyl alcohol with platinum/hydrogenO
- After the absorption of hydrogen has ceased, it is filtered
off from the catalyst and the filtrate is concentrated.
There remain~ the title compound as a dark brown viscous
oil. Yield 10.5 g (100 % o~ theory)~ ?
The benzoate ~from isopropanol) melts at 186-190 (dec.).
- in
Using the mode of operation described in Example 12
one obtains from 5.0 g 2-~4-chlorobenzyl~-perh~droazepin,
.
: : . . ~- . . .
. ~
, . , - '.: . ~ ~ ,., '. . ~ , , ,:

- 53
4.0 g of anhydrous potassium carbonate and 3.0 S of
sec . butyl bromide1 3.2 g of the title compound.
azepin
U~ing the mode of operation described in Example 12
one obtains from 500 g of 2-(4-chlorobenzyl)-perhydro-
azepin, 4.0 g of anhydrous potas~ium carbonate and 3.6 g.
of neopentyl bromide, 3.9 g of the title compound.
.
Exam~le 20
2-(4-chlorobe~yl)-l~cyGlohe~ylperhy~roazepin
Using the mode of operation described in Example 12
one obtains from 5 g of 2-(4-chlorobenzyl~-perhydroazepin,
3.1 g of anhydrous potassium carbonate and 4 g of cyclo-
hexyl bromide, 2035 g of the title compound.
Ex~ le 2~
1-methyl-2-(4-nitroben~yl)-perhydroaz~pin
Using the mode of operation described in Example 12
one obtains from 2.34 g of 2-~4-nitrobenzyl)-perhydroazepin,
:
1.4 ~ of anh~drous potassium carbonate and 1.5 g of methyl
~; iodide, 1.9 g of the title compound as a red oil.
.
: '' , '

- 5~ -
2- ( 4-aminobenzyl ) -1-methyl-perhyd oazepi
Usin$ the mode of operation de-~cribed in Example 17
one obtains from 3.45 g of 1-methyl-2-~4-nitrobe~zyl)-
perhydroazepin by hydrogenation with PtO2~hydrogen 2-9 S
of the oily title compound~
Example 23
~_=~
2.18 g of 2-(4~aminobenzyl)-1-methyl-perhydroazepin,
2.0 g of anhydrous potassium carbonate and 3.1 g of die*hyl
~ulphate are stirred at. 140 for 7 hours. After cooling,
the suspen~ion is mixed with water and poured into caustic
soda solution and extracted with diethyl ether. The organic
phase is dried over sodium sulphate and the ether is
distilled off. Residue 1.9 g (70 % yield)~
Uqing the mode of operation described in Example 12
one obtains from 4.0 g of 2-benzyl-perhydroazepin, 2.9 g
of anhydrous pota~-~sium carbonate and 3.3 g of methyl iodide,
2.4 g of *he title compound with a BP of 68 at 0.003 mm Hg
(56 % of theory).
~,
.
'`. .
., '~
."' ' ' ' ' ' , . ' ''
. ' , ', ~' ' ' ,, , ' '

~ 55 ~ 3'~'~
The picrate melts at 116-118.
Example 2~
2-(4-bromobenzyl)-1-meth~lper~y~roa~in
2.03 g of 2-benzyl-1-methyl-perhydroazepin and 50 mg
of iron powder are mixed with 10 mmoles of bromine at
room temperature. It is stirred for 2 hours, rendered
alkaline with caustic soda solution, and the base is
extracted with ether, distilled and in thi~ way ons ob-
tains 2-(4-bromobenzyl)-1-methyl-perhydroazepin as an
oily and almosi colourless liquid with a BP of 108 at
0.003 mm Hg.
Example 26
. ,
'' _
` 5.0 g of 2-(3,4-dimethoxybenzyl)-1-methyl-perhydro-
azepin are boiled under a reflux in a mixture of 45 mls of
acatic ac:d and 45 mls of 48 % hydrobromic acid for 40
hours. The bulk of the acid is removed by distillation in
vacuo, tha residue is taken up with iced water and alkalised
with soda solution. A~ter extracting the base for several
hours with ether, after distilling off the ~olvent the
residue obtained (4.0 g) is converted into *he hydrochloride
with methyl alcohol/ethereal hydrochloric acid. Yield 3.0 g.
:
~ .. - . . . .
,
.. ': :
.
' ' ' ~ ' ' , '

~ ~4 ~7
- 56 -
Example 27
b z
Using the mode of operation de~cribed in Example 2
one obtai~.~ from 50 g of 2-dimethyl2mino-1-methyl-4,5,6,7-
tetrahydro-3H-azepinium methylsulphate1 35.6 g of ethyl
3,4,5-trimethoxyphenyl acetate and a solution of 4.32 g
o~ sodium in lG0 mls of ethanol, 14.23 g of the title com-
pound as a vi3cous oil (28 % of theory).
Example 28
2~benzyl-1-cycloprop~lcarbonyl-perhydroaze~in
To 7.0 g of 2-benzyl-perhydroazepin and 4.1 g of
triethylamine in 70 ml 5 of dichloromethane one adds drop
by drop at 0 to 8 4.3 g of cyclopropanoic acid chloride
i~ 40 mls o~ dichloromethane. The stirring i~ continued
for a further 2 hour~ at 0 , it is mixed with 300 mls of
water, the organic pha~e is separated, it is extracted again
with dichloromethane, the combined organic pha~es ar0
wa~hed with dilute h~drochloric acid and soda solution,
dried o~er sodium sulphate and concentrated t~ form a
viscous oil. Yield 9.2 g (97 % of theory).
.~ , .
:
:
..
,.. . . . .
~; . ~ : . :
. ' . ~ ' .
, ~ .
.

~ 57 -
Example 29
9.0 g of 2-benzyl-1-cyclopropylcarbonyl-perhydroazepin,
dis~olved in 80 ml~ of tetrahydrofuran, is added drop
by drop whilst stirring at 0 o~er a period of 10 minutes
to a suspension of i.30 g of lithium aluminium hydride
(= lithium hydridoaluminate) in 30 mls of tetrahydrofuran.
Then it is boiled for 1.5 hours under a reflux, a further
2.0 S of lithium aluminium hydride is added, it is boiled
for a further 3.5 hours under a reflux and after cooling
one adds carefully 300 mls of water and extract~ 3 times
with 50 mls of ether each time. The combined ether solutions
are washed with saturated common salt solution, it is dried
over sodium sulphate and the residue is distilled after
evaporating off the solvent i~ vacuo. Yield 5.o9 g with
a BP of 115 at 0.01 mm Hg.
'
Using the mode of operation described in Example 28
one obtains from 6 ~ of 2-benzyl-perhydroazepin, 4~14 g of
triethylamine and 2065 g of acetyl chloride, 5~8 g of a
~iscou~ oilO
-
... .

- 58 -
l-et ~ Z-benzyl-perhydroazepin
Using the mode of operation described in Example 29
one obtain~ from 2.5,g of 1-acetyl-2-benzyl-perhydroazepin
and o.80 g of lithium aluminium hydride 1.2 g of an oil
with a BP of 90-95 at o.oo8 mm Hg.
Exam ~
'' ' ~
U~ing the mode of operation described in Example 28
one obtain~ from 6 g of 2-(4-chlorobenzyl)-perhydroazepin,
4.14 g of triethylamine and 4.30 g of cyclopropanecarboxylic
acid chloride 6.2 g of a vi~cous light yellow oil.
2-(4-chlorobenzyl~-l-cyclo~ropy~methyl-perhydroazepin
Uqing the mode of operation de~cribed in Example 29
one obtain~ from 5.0 g of 2-(4-chlorobenzyl)-1-cyclopro-
pylcarbonyl-perhydroazepin and 104 S of lithium aluminium
hydride 3.2 g of a colourle~s oily liquid with a BP of
100-105 at 0.01 mm Hg.
,
'
' :

- 59 - ~.~ 3~i~
~,,2~
d~
To a solution of 1.9 g of 2~ aminobenzyl)-1-methyl-
perhydroazepin and 1 g of triethylamine in 10 mls of
benzene one adds drop by drop a solutic~n of 0.75 g of
acetyl chloride in 5 mls of benzene~ After an hour one
concentrates the product, takeR it up with water and
ether t collects the organic phase and concentrates it.
~e~
2-(4-methoxybenzyl)-perhydro-zepin
6.5 g of caprolactimmethylether, 5~0 g of 4-~ethoxy-
b~nzyl cyanide and 0.5 g of 1,5-diazabicyclo[5.4.0~undec-
5-ene are stirred under nitrogen for lo hours at 125 ,
~olatile components are removed in high vacuum and the
vi~cou~ dar~ residue ~2-[(~-cyano)-4-methoxybenzylidene]-
perhydroazepin) is boiled with 50 mlq of concentrated
hydrochloric acid under a re~lux lmtil the evolution of
carbon dioxide cea~es. After cooling, it is alkalised whilst
cooling, extracted with ether and the ether extract after
drying over sodium sulphate is concentrated. The 2-(4-
methoxybenzyl)-4,~,6,7-tetrahydro-3H-azepin so obtained
is hydrogenated with platinum/active carbon/hydrogen in ethyl
alcohol, filtsred o~f from the catalyst, concentrated
' ' ' '
.
; .

- 60 ~ 7~
and distilled. One obtains the title compound with a BP
of 100-106 at 0~01 mm Hg~
Example 36
2-(3~methoxyben~yl ~ rhydroazepin
Using the mode of operation described in Example 35
one obtains from caprolactimmethyl ether, 3-methoxyben3yl
cyanide and 1,5-diazabicyclo~5.4.0]-undec-5-ene the title
compound as an oil with a BP of 98-103 at 0.01 mm Hg.
Example 37
2-(4-methox~enz~l)-1-meth~l-perhydroazepin ~,
.
Using the mode of operation d~cribed in Example 12
one obtains from 2.19 g of 2-(4-methoxybenzyl)-perhydroaze-
pin, 2~9 g of methyl iodide and 2~1 g of anhydrous potassium
carbona~e the title compound as a lig~t-coloured oil.
.
~ .
2-(3-methoxybenzyl)-1-meth~l-perh~droazepin
: Using the mode of operation described in Example 12,
one obtains from 2-(3-methoxybenzyl)-perhydroa~epin, methyl
iodide and pota~sium carbonate the title compound as an
oil with a BP of 110-115 at 0.01 mm Hg.
.
'
:
~ ' ' .
.:

- 61 -
Example ~2
-(4-chlorobenzyl)-1-[3-(4-fluorobenzov~ pr
2 g of 2-~4-chlorobenzyl)-perhy~roazepill, 2.7 g of
~~chloro-4-fluoro-butyrophenone, 1.89 g of potassium
carbonate and 10 mls of methylethylketone are boiled under
a reflux for 70 hours and after cooling are mi~ed with
25 mls of water and 25 mls of ether~ The ether phase is
collected, dried over sodium sulphate, concentrated and
dried in high vacuum at 80. Yield 1.0 g of visc:ous
light-brown oil.
Example 40
~ .
0.5 g of 2-(4-chlorobenzyl)-1-~3-(4~fluorobenzoyl)-
propyl]-perhydroazepin are heated with 1 ml~ of hydrazine
hydrate, 0.5 g of potas3ium hydroxide and 5 mls of tri
glycol for 2 hours at 165 and after cooling are mixed
with water and ether. The ether phase is dried over sodium
sulphate and then concentrated. Yield 0.3 g of viscous oil.
.
.
,'
- : - :-
.-:
~ ~ I

- 62 ~ 3~7~
Using the mode of operation described in Example 12,
one obtains from 5 g of 2-~4-chlorobenzyl)-perhydroazepin,
3.2 g of anhydrous potassium carbonate and 2.83 g of benzyl
chloride, 3.95 ~ of the oily title compound.
Example 42
2-~4-chlorobenz ~ rhydroazepin
:
3.0 g of 1-b,enzyl-2-(4-chlorobenzyl)-perhydroazepin
are hydrogenated in 50 mls of ethyl alcohol with 10 %
of palladium on active carbon. A~ter filtering o~f the
catalyst, it is concentrated and the residue is con~erted
into the hydrochloride wi-th ethereal hydrochloric acid,
and after this has been recry~tallised from methyl alcohol/
ether it melt3 at 176~178.
Example 43
4.00 g of ~-(4-chlorobenz~l)-1-methylperh~droazepin are
boiled under a reflux for 5 ho~rs with 20 mls of ethyl
chloro~ormate, the excess chloroformate ester is distilled ~.
off and the residual crude 1-ethoxycarbonyl-2-(4-chloro-
benzyl)-perh~droazepin is boiled with 100 mls of n-butanol

63
and 8 g of potassium hydroxide for 20 hours. After mixing
with ~ater the organic phase i~ separated and the aqueous
phase is extracted with dichloromethane. The combined
organic phases are concentrated and the oily residue is
con~erted with ethereal hydrochloric acid into the hydro-
chloride, which is recrystallised from methyl alcohol~
ether. Yield 2.2 g (50 % of theory) with an MP of 177-~78.
Analogou~ly, by reacting 1-benzyl~2-~4 chlorobenzyL)-
perhydroazepin with ethyl chloroformate ~ollowed by sa-
ponification with potas~ium hydroxide in butyl alcohol
one obtains the title compound.
~ '.
2-~(~-cyano)-2-chlorobenzylidene ~ erhydroaze~in
U~ing the mode o~ operation described in Example 9
one obtain~ ~rom 5.0 g of 2-chlorobenzyl cyanide, 5.5 g
of caprolactimmethyl ether and 0.5 g of diazabicyclo-
[5.4.0~undec-5-ene, 4.5 g of the oily title compound.
~ .
2-(2-chlorobenzyl)~erhydroazepin
Using the mode of operation described in Example lV,
one obtains from 4~0 g of 2-[(~-cyano)-2-chlorobenzylidene]-
~ perhydroazepin 1.9 g (52 %) of the title compound wi*h a
" ,,.
.
.
~ ' '
~.: ., :

- 64
BP of 100-106 at 0.05 mm Hg.
,
Example 46
2- L(~- cyano)-3-chlorobenzy~ e~-~erhydroazepin
Using the mode of operation described in Example 9
one obtains from 5.0 g of 3-chlorobenzyl cyanide, 5.5 g
of caprolactim methyl~an~ O.S g of diazabicyclo[5.~0]-
undec-5-ene 4.5 g of the oily title compound.
Example 47
2-(3-chlorobenzyl)-perhydroazepin
U~ing the mode of operation described in Example 10,
one obtains from 4.0 g of 2-r(~-cyano)-3-chlorobenzylidene]-
perhydroazepin 2.2 g (60 %) of the title compound with a
BP of 98 io3 at 0.01 mm Hg.
Example 48
2-(~-chlorobenzyl)-1-meth~l-perhydroazepin
Using the mode of operation déscribed in Example 12
one obtains from 2.5 g of 2- ( 3-chlorobenzyl)-perh~dro-
azepin, 1.5 g of anhydrous potassium carbonate and 1.5 g
of methyl iodide 2.0 g of the title compoundO
~ ,, .
'' ~ '
': ' ,

- 6
Example 49
~ lene~
hydroazepin
Using the mode Qf operation described in Example 2,
one obtain~ from 80.2 g of 2-dimethylamino-1-methyl-
4,5,5,7-tetrahydro-3H-azepinium meth~lsulphate and 40 g of
ethyl 2-chlorophenylacetate the title compound as a
dark viscous oil.
'
Example 50
2-(2-chlorobenzyl)-1-methyl-perhydroaze~__
Using the mode of operation described in Example 6,
one obtains from 2-[~-tethoxycarbonyl)-2-chlorobenzylidene]-
1-methyl-perhydroazepin the title compound as a light~
coloured oil with a BP of 134 at 0.01 mm Hg.
The picrate (from ethyl alcohol) melt~ at 123~12S.
Example'51
7-(4-chloroben~yl)-perh~droazepin-2-one
To an ice-cold ~olution of 4.47 g of 2-(4-chlorobenzyl)-
cyclohexanone in 100 g of polypho~phoric acid one add3
2.6 ~ of sodium azide whil~t stirring. The mixture i~
stirred for another 1.5 hours at 0 and for a further
8 hours at room temperature, poured into ice water and
.
. , ::: , .
.

_ 66 -
extracted with methylene chloride~ After drying the organic
phase over sodium sulphate the solvent is distilled off~
There remain 2.85 g of tha title compound as a light
brown oil~
'` '
O.5 g of lithium aluminium hy~ide are added to a
~olution of 2.8 g 7-(4-chlorobenzyl~-perhydroazepin-2-
one in 30 ml of tetrahydro~uran. Th0 mixture is boiled
under a raflux for 16 hours, cooled and carefully treated
with ice-water. After extraction with diethyl ether, drying
over sodium sulphate and concentrating the oily residue
is distilled in a ~acuum. One obtains 1.8 g of the title
~ compound with a BP of 90-92 at 0005 mm Hg.
:: `
2-(4-aminobenzyl)-perhydroazepin
3.72 g of 7-(4-nitrobenzyl~-perhydroazepin-2-one are
hydrogenated in 50 m1s of ethyl alcohol with platinum/
hydrogen. After t~,e absorption of hydrogen ha~ ceased,
it is filtered off from the catalyst and the ~iltrate
is concentrated. The thus obtained 7-(4-ami~obenzyl)-
perhydroazep~n-2-one is dissolved in tetrahydro~uran,
:
.
.
,

- 6 7 ~ 3 .f f-~
680 mg of lithium aluminium hydride are added and the
mixture i~ boiled under a reflux. After cooling it is
treated with ice-water and extracted with die*hyl ether~
The organic phase i~ dried over sodium ~ulphate and con-
centrated. There remain 2.0 g of the brown oily title
compound.
The benzoate (from i~opropanol) melts at 186-189(dec.)0
2-(2-met_oxybenzyl)~perhydroaze~_n
Using ths mode of operation described in Example 52
one obtains from 2~8 g of 7-(2-methoxybenzyl)-perhydro-
azepin-2-one and 0.5 g of lithium alumi~ium hydride 1.5 g
o~ t~ title compound as oil with a BP of 95-100 at 0.01
mm Hg.
:,'
2-(4-methylbenzyl)-perhydroazepin
Using the mode of operation de~cribed in Example 52
one obtain~ ~rom 2.8 g of 7-(4-methylben~yl)-perhydroazepin-
2-o~e and 0.5 g of lithium aluminium hydride 1.6 g of
the title compouDd as oil with a BP of 82-85 at 0.01 mm Hg~
. .

- 68 -
E~a!nple 56
A solution of 10 mmol of n-butyllithium in n-hexane
is added to a solution of 1.01 g of diisopropylamine in
100 ml of tetrahydrofuran at -78 and passing argon. The
mix~ure is stirred for 5 minutes at room temparature and
then cooled down again to -78. A solution of 1.28 g of
N-nitrosoperhydroazepin is added and stirred for ~ hourO
Then, ~ol S of 4-chlorobenzyl bromide in a small a~lount
of diethyl ether are added. A~ter stirring for another
5 hours at -78 5 ml of glacial acetic acid are added.
The mixture is warmed up to room temperature poured into
100 ml of dichloromethane saturated sodium chloride solution.
The organic pha~e is freed ~rom the sol~ent and then dis-
~ol~ed in methanol. A~ter addition of 2 g of R~ney nickel
freshly prepared, hydrogen is pa~sed through the Yolution
whilst stirrlng vigorously. Catalyst is filtered off and
washed with methanol, the methanolic filtrate i5 concen-
trated. By treating the oily reqidue with ethanol/ethereal
hydrochloric acid ona obtains the hydrochloride of the
title compound; m.p. 176-178 .
.
,~
,~
.

- 69 ~$~ P4~
Charse ~or 100 litres (ampoules)
1. 2-(4~chlorobenzyl)-1-isopropyl-perhydroazepin 2.500 kg
2. Mannitol 4.000 kg
3. Twice-distilled ~a~er up to 100 litres
1 is di~solved in 80 litres of ~ater with the addition
of the equivalent quantity of hydrochloric acid and then
2 is added. The solution is adjusted to a pH of 7.0 - 0.5
and then made up with the rest of the water. The solution
is filtered sterile over a filter and packed into 2-ml
ampoules under germ-free conditions.
~ '
Char~e for tablets
1. 2-(4-chlorobenzyl)-perhydroazepin hydrochloride 10~0 ~g
2~ Glutamic acid 5.0 kg
3. Maize starch 38.o kg
4. Milk su ar 37.0 kg
e~as.j~ ~
5. ~n~fft}- 1.5 kg
6. Sodium lauryl sulphate 2.0 kg
7. Gelatin 2.5 kg
8~ Glyceri~ ~-5 kg
9. Talcum 2.5 kg
lO.Magnesium stearate 1.0 kg
: ~r~de IY)arl'
, ~: '' . '

- 70 ~
~'
2 is mixed with 5 kg of 4 and ground finely. This
mixture is mixed with 1 and 30 kg of 3, the rest of 4, 5
and 6, and qifted. This mixture is moistened with a solu-
tion of 7 and 8 in 35 litres of water and pas~ed through
a strainer with a mesh of 1.25 mm~ A~ter drying, the
granulate is mixed with the rest of 3, 9 and 10, and
pressed into tablets of 200 mg.
Examp~e 59
Charga for tablets
1. 2-~4-aminobenzyl)-perhydroazepin benzoate 30.0 kg
2. Cellulose (Rehocel~ 8.5 kg
3. Milk qugar 25.0 kg
4. Maize starch 22.2 kg
5~ Poly~rinylpyrrolidone (Kollido~) 25) 3.0 kg
6~ Carboxymethylcellulose tPrimojel)8~5 kg
7~ Talcum 2 7 5 ~
. .
8. Magnesium stearate 0. 3 kg
; 1, 2, 3 and 4 are mixed, moi~tened with 5 (dissolved
in 15 litres of water) and granulated~ After this it is
pre-dried in t~e dr~ing oven at 50 and then pa~sed through
a sieve~ Th~ granulate is dried to a relative humidity
of 45 t~ 50 % and after the addition of 6, 7 and ô and
oareful mixing is pres~ed into tablets with a weight of
.~ 100 mg.
.,
:
: : : ,: : ~. ..
: :
:, .: , : .
: : :
.

- 71 - ~ `7
Example 60
Charse for tablets
1. 2-(4-chlorobenzyl)-perhydroazepin hydrochloride 25.0 k~
2. Cellulose ~Rehocel~ 8.5 k~
3. Milk sugar 300 kg
4~ Maize starch 22.2 kg
5. Polyvinylpyrrolidone (Kollidon~ 25)3.0 kg
6. Carboxymethylcellulose (Primojel)8.5 kg
7. Talcum 2.5 kg
8. Magnesium stearate 0.3 kg
1, 2, 3 and 4 are mixed, moistened with 5 (dissolved
in 15 litras of water) and granulated. After this it is
pre-dried in the drying cabinet at 50 and then passed
through a sieve. The granulate is dried to a relative
humidity of 45 to 50 % and after the addition of 6, 7,
8 a~d careful mixing is pressed into tablets with a
~ weight of 100 mg,
.,