PROCESS FOR THE PREPARATION OF 2-AMINO-BENZYLAMINES

SYNTHESE D'AMINO-2 BENZYLAMINES

English Abstract

2-amino-benzylamine ABSTRACT OF THE DISCLOSURE
The invention relates to a new process for the
preparation of 2-amino-benzylamine derivatives having
valuable pharmacological properties, in particular a
secretolytic and/or antitussive activity. The process
comprises the reaction of the corresponding 2-amino-
benzyl alcohol with an appropriate amine, either the
amino group being acylated or the reaction being
performed in the presence of an organic acid. Examples
of the proparation of certain 2-amino-benzylamine by
means of the new process are given.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of compounds of general formula
(I)
<IMG>
(wherein Hal represents a chlorine or bromine atom, R1 represents a hydrogen,
chlorine or bromine atoms R2 represents a hydrogen atom or an alkyl group
containing 1 to 3 carbon atoms and R3 represents a hydroxycyclohexyl or
morpholinocarbonylmethyl group, with the proviso that when R3 is a hydroxy-
cyclohexyl group R2 is not an alkyl group) and pharmaceutically acceptable
acid addition salts thereof which comprises reacting a compound of formula
(II)
<IMG>
(wherein Hal and R1 are as hereinbefore defined and R4 and R5, which may be
the same or different, each represent a hydrogen atom or an organic acyl
group) with a compound of formula
<IMG> (III)

(wherein R2 and R3 are as hereinbefore defined) whereby a
compound of formula I is obtained and if desired subsequently
converting the compound of formula I thereby produced
into a pharmaceutically acceptable acid addition salt thereof.
2. A process as claimed in claim 1 wherein a compound
of formula I is used in which both R4 and R5 represent hydrogen
atoms and wherein the reaction is effected in the presence
of an organic acid.
3. A process as claimed in claim 2 wherein the organic
acid used is acetic acid, butyric acid, valeric acid, trimethy-
lacetic acid or capronic acid.
4. A process as claimed in claim 1 wherein the reaction
is effected in the presence of a solvent.
5. A process as claimed in claim 4 wherein an excess of
the compound of formula III is used as solvent.
6. A process as claimed in claim 2 or claim 3 wherein
an excess of the organic acid is used as solvent.
7. A process as claimed in claim 1 or claim 2 wherein
the reaction is effected at temperatures from 100 to 200°C.
8. A process as claimed in claim 1 wherein the compound
of formula II is prepared immediately prior to the reaction and
is not isolated before use.
9. A process as claimed in claim 1 wherein the groups
R4 and/or R5 in the compound of formula II represent acetyl,
butyryl, benzoyl or p-chlorobenzoyl groups.
11

10. A process according to claim 1 in which Hal is a bromine atom
in the 3-position and R1 is a bromine atom in the 5-position, R2 represents
a hydrogen atom and R3 represents a trans-4-hydroxycyclohexyl group.
11. A process for the preparation of 2-amino-3,5-dibromo-N-(trans-4-
hydroxycyclohexyl)benzylamine and its hydrochloride which comprises reacting
2-acetylamino-3,5-dibromobenzyl alcohol or 2-diacetylamino-3,5-dibromobenzyl
alcohol, 2-butyrylamino-3,5-dibromobenzyl alcohol or 2-p-chlorobenzoylamino-
3,5-dibromobenzyl alcohol with trans-4-amino-cyclohexanol, and when the
hydrochloride is required reacting the base so obtained with hydrogen
chloride.
12. A process for the preparation of 2-amino-3,5-dibromo-N-(trans-4-
hydroxy-cyclohexyl)benzylamine and its hydrochloride which comprises reacting
2-amino-3,5-dibromobenzyl alcohol with trans-4-amino-cyclohexanol in the
presence of butyric acid, acetic acid, valeric acid, capronic acid or
trimethylacetic acid, and when the hydrochloride is required reacting the
base so obtained with hydrogen chloride.
12

Description

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The imention relates to a new process for the
preparation of 2-amino-benzylamines havi~g interesting
pharmacologici~l properties.
United States Patent Specifications Nos. 3,546~713 and
3,712,924 describe and claim inteI alia 2-amino-benzylamines of
general formula
1 ~ N2 3
Ha
i NH2
,; . .
(wherein Hal represents a chlorine or bromine atom,
Rl represents a hydrogen, chlorine or bromine atom,
R2 represents a hydrogen atom or an alkyl group containing
from I to 3 carbon atoms and R3~represents a hydroxy~
cyclohexyl or morpholin~GaIb~ethyl group) and
physiologically compatible aoid addition sal~ts thereof,
and also processes for their preparation.
In general the compounds of general formula I as
hereinbefore defined and acid addition salts ~hereof ~`
possess valuable pharmacological properties~ in particular
a secretolytic and/or antitussive activity.
It is an object of the present invention to provide
~ .
.
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.
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a new process for the preparation of compounds of general formula I (as
hereinbefore defined and with the additional proviso that when R3 is a
hydroxycyclohexyl group R2 is not an alkyl group) and acid addition salts
thereof.
Thus according to the presen~ in~ention there is provided a
process for the preparation of compounds o:F general formula I as hereinbefore
defined, including the proviso that when R3 is a hydroxycyclohexyl group R2
is not an alkyl group, and pharmaceutically acceptable acid addition salts
thereof which comprises reacting a compound of formula
Rl ~ CH2H (II)
Hal ~ N~-R4
, , .
~wherein Hal and Rl are as hereinbe~ore defined and R4 and R5, which may be
the same or different, each represent a hydrogen atom or an organic acyl ~. :
group) with a compound of formula
,,~' 2 (III) :
H - N \ -`~
3 ~ .
Cwherein R2 and R3 are as hereinbefore defined) whereby a compound of formula I
i5 qbtained and if desired subsequently converting the compound of formula I
thereby produced into a pharmaceutically acceptable acid addition salt thereof.
Where R4 and R5 represent hydrogen atoms,
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the reaction is carried out in the presence of an
organic acid whereby the cdesired compound of formula
I is obtained.
Using the process according to the invention we
have prepared compounds of general formula I and acid
addition salts thereof in good yield.
The reaction is preferably effected in the presence
of a solvent~ usually a high boiling solvent such as
tetraline or xylene. Alternatively an excess of the
eompound of formula III and/or an excess of the organie
aeid may be used to serve as solvent.
In general the reaetion is effeeted at temperatures
from 100 to 220 C. If a compound o~ formula II wherein
both R4 and R5 represent hydrogen atoms is used the
reae~ion is preferably effeeted at temperatures from
140 to 180 C. If R4 and/or R5 in the eompound of formu]a
II represent acyl groups the reaction is preferably
effected at temperatures from 120 to 190C.
The organic acid when used is aclvantageously an
aliphatie acid for example acetic acid, butyric aeid,
valerie acid, trimethylacetie aeid or eapronie aeid~
Where the groups R~ and/or R5 in the eompound
of formula II represent organie aeyl groups, these
groups may for example be aeetyl, butyryl~ ben~oyl or
p-ehlorobenzoyl groups.
The compounds of general formula I obtained may,
i ,:
, - .; . .:

~ if desired, be subsequently convarted into their acid
; addition salts, preferably their physiologically compatible
acid addition salts with inorganic or organic acids.
Suitable acids for this purpose include for example
hydrochloric acid, hydrobromic acid~ sulfuric acid~ ;
.~ . . .
phosphoric acid~ lactic acid, citric acid and maleic
acid.
The compounds of general formula II used as starting
.,~ . ... ~ , .
materials may be prepared from the corresponding ben~yl
alcohols~ which themselves may be conveni~ntly prepared
by reduction of the corresponding aldehydydes with sodium
borohydride. Compounds of general formula II wherein
R~ and R5 represent hydrogen atoms may if desired be
subsequently acylated by reaction with appropriate acyl
halides in the presence of pyridine, the simultaneously
formed esters being saponified under basic conditions.
. .
The s~arting materials of general formula II obtained
; may, if desired, be reacted without previous isolation.
It is surp~ising that the new process according
to~t~e invention in general produces compounds of general
formula I in such good yields since the analogous reaction
.
of an unacylated ben~yl alcohol of formula II and an
amine of formula III or the hydrochloride thereof in
the absence of an organic acid does not yield the desired
, .
product of formula I.
The following Examples serve to illustrate the
. .. .
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new process according to the invention:
Example 1
; ~ r
benzylamine
5.8 g (0.018 mol) of 2-acetylamino-3,5-dibromo-benzyl
alcohol were stirred with 2.3 g (0.020 mol~ of trans-4-
amino-cyclohexanol in 20 ml of tetraline at 175C for 4
hours. Subsequently, the solution was evaporated in vacuo
at 120C. The residue was dissolved in ether, extracted
three times with water and the organic layer was dried
with sodium sulfate and evaporated to dryness, The
residue was dissolved in absolute ethanol and acidified with
ethanolic hydrochloric acid to yield 2-amino-3,5-dibromo-N-
(trans-4-hydroxy-cyclohexyl)-benzylamine hydrochloride
which was crystallized by addition of etherO
Yield: 4.4 g (59.0 % of theory3. After recrystallization
from absolute ethanol the compound melted at 233-234.5 C
(decomp.).
Example 2
M.p.: 116 to 118 C
Prepared from 2-benzoylamino-6-chloro-benzyl alcohol and
sarcosine morpholide analogously to Example 1
2-~mino-3,5-dibromo
benz~lamine

1~:)5~
.. .
M~po of the hydrocholride: 233 to 234.5 C (decomp).
Prepared from 2-diacetylam:;no-3,S-dibromo-benzyl
; alcohol and trans-4-amino-cyclohexanol analogously to
Example 1.
Example 4
; .
.
506 g (0.02 mol) of 2-amino-3,5-dibromo-benzyl
alcohol were stirred with 11.5 g (OolO mol of trans-4-
amino-cyclohexanol and 8.8 g (OolO mol) of butyric
acid at 165 C. The reaction solution was then taken up
ln ether, extracted twice with water and the organic
layer was dried with sodium sulfate and evaporated to
dryness. The residue was dissolved in absolute ethanol
and ether (1:1) and the solution was acidfied with
e*hanolic hydrochloric acidO 1~5 g of a by-product
first crystallized out and after further addition of
ether, 3.5 g (42% of theory) of 2-amino-3~5-dibromo-
N-(trans-4-hydroxy-cyclohexyl)-benzylamine hydrochloride ~-
were obtained.
M.p.: 233 to 234 C (decomp.)
- Example 5
2-Amino-6-chloro-N-methyl-N-morpholinocarbonylmeth~
benzyliamine
M.p.: tl6 to lt8 C~
Prepared from 2-amino-6-chloro benzyl alcohol~
sarcosine morpholide and butyric acid analogously to ~xample 4
--7--
-

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xample 6
2-Amino-3,5-dibromo-N-(trans-4-hydroxy-cyclohexyl)-
benzylamine
M.p. of the hydrochloride: 233 to 234.5 C (decomp.).
Prepared from 2-butyrylam.Lno-3,5-dibromo-benzyl
alcohol and trans-4-amino-cyclohexanol analogously
to Example 1.
Example 7
10 ~
~I.p. of the hydrochloride: 233 to 234.5 C (decomp.).
Prepared from 2-p-chlorobenzoylamino-3,5-dibromo-
benzyl alcohol and trans-4-amino-cyclohexanol analogously
to Example 1.
Example _
,
M.p. of the hydrochloride: 233 to 234.5 C (decomp.)
Prepared from 2-amino-3~5-dibromo-benzyl alcohol~
20 trans-4-amino-cyclohexanol and acetic acid analogously to
Example 4.
Example 9
2_~ml ~3, ~di~r~-N-(trans-4-hydroxy-cyclohexyl)-
benzyl_~ine
M.p. of the hydrochloride: 233 to 234.5 C (decomp.).
Prepared from 2-amino-3~5-dibromo-benzyl alcohol,
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- ' ' ' . , ' , ~ , ' ', ,` , ~, ., ' . - , . ` ' ' , . :
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trans-4-amino-cyclohexanol and valeric acid analogously
to Example 4.
Example 10
2-Amino 325-dibromo-N-~trans-4-hydroxy-cyclohexyl)-
benzylamine
M.p. of the hydrochloride: 233 to 234.5 C (decomp.).
Prepared from 2-amino-3,5-dibromo-benzyl alcohol,
trans-4-amino-cyclohexanol and capronic acid analogously
to Example 4.
Example 11
~-Amino-3?5-dibromo-N-~trans 4-hydroxy-
ben~ylamine
M.p. of the hydrochloride: 233 to 234.~ C (decomp.).
Prepared from 2-amino-3,5-dibromo-benzyl alcohol,
trans-4-amino-cyclohexanol and trimethylacetic acid
analogously to EKample 4.
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