PROCESS FOR THE PREPARATION OF 2-ACYLAMINO-BENZYLAMINES

ACYLAMINO-2 BENZYLAMINES

English Abstract

ABSTRACT OF THE DISCLOSURE
The invention relates to a new process for the
preparation of certain 2-acylamino-benzylamine
derivative having interesting pharmacological properties,
in particular an antiussive and respiration
stimulating activity. The new process comprises the N-
alkylation of the corresponding secondary benzylamine
compounds. Examples of the preparation of certain
2-acylamino-benzylamine derivatives 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
<IMG> (I)
(wherein Hal represents a chlorine or bromine atom, R1
represents an alkyl group with 1 to 3 carbon atoms and
R2 represents a morpholino or isopropylamino group) and
pharmaceutically acceptable acid addition salts thereof
which comprises alkylating a compound of formula
<IMG> (II)
(wherein R2 represents a morpholino or isopropylamino
group and Hal represents a chlorine or bromine atom) and,
11

if desired, subsequently converting the compound of
formula I obtained into a pharmaceutically acceptable
acid addition salt thereof.
2. A process as claimed in claim 1 wherein the
alkylation is effected with an alkylating agent comprising
a compound of formula
R1 - X (III)
[wherein R1 represents an alkyl group having from 1 to 3
carbon atoms and X represents a chlorine, bromine or
iodine atom or a group of formula -O-So2R3 (wherein R3
represents a methyl or 4-methylphenyl group) .
3. A process as claimed in claim 2 wherein the reaction
is effected in the presence of an inert organic solvent.
4. A process as claimed in claim 2 wherein the
reaction is effected in the presence of an inorganic base.
5. A process as claimed in claim 4 wherein the base
comprises sodium hydroxide, potassium hydroxide or potassium
tert-butoxide.
6. A process as claimed in claim 3 wherein the
reaction is effected at temperatures from 0°C up to the
boiling temperature of the solvent used.
7. A process as claimed in claim 1 wherein the alky-
12

lation is a methylation and is effected by heating the compound of formula II
with formaldehyde and formic acid.
8. A process as claimed in claim 7 wherein the methylation is effected
in the presence of a solvent.
9. A process as claimed in claim 7 or claim 8 wherein the methylation
is effected at temperatures from 80 to 100°C.
10. A process according to claim 1 in which Hal is chlorine in the
6-position, R1 represents a methyl group and R2 represents a morpholino group.
11. A process for the preparation of 2-benzoylamino-6-chloro-N-methyl-
N-(morpholino-carbonylmethyl)-benzylamine which comprises methylating
2-benzoylamino-6-chloro-N-(morpholino-carbonylmethyl)-benzylamine.
12. A process according to claim 11 in which the methylation is
effected by reaction with methyl iodide, a mixture of formaldehyde and
formic acid, or p-toluenesulfonic acid methyl ester.
13

Description

5 ~3
'rhe lnvention relates to a new process for the
preparation of 2-acylamino-benzyamine derivatives having
int,eresting physiologica] activities.
British Patent Noc 19 098,140 describes and claims
inter alia 2-acylamino-benzylamine compounds of general
.
' formula
Hal ~ ~ ~ ~1 (1)
NH - CO
, .
(wherein Hal represents a chlorine or bromine atom, Rl
represents an alkyl group with 1 to ~ carbon atoms and
R2 represents a morpholino or ~sopropylamino group) ~nd
. . .:
acid addition salts ~hereof and also ~ertain processes
~, for their preparatlon.
' In general the compounds of the general formula I
- and their physiologically compatible ~cid addition salts
possess valuable pharm~cological prop~rties, especially ar.
antitussi~e and respiration stimulati~g activity.
- 2 -
. . . .
.
. .

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It is an object of the present invention to provide
a new process for the preparation of compounds of general
formula I (as hereinbefore defined) and acid addition
salts thereof.
~ ccording to the present invention there is thus
provided a process for the preparation of compounds of
general formula I (as hereinbefore defined) and pharma-
ceutically acceptable acid addition salts thereof which
comprises alkylating a compound of formula
~ 2 ~ H
Hal-- _
, , CH2 - CO - R2 ,~
`i~' ~ NH - CO (II)
(~herein R2 and ~al are as hereinbefore defined) and if
desired converting the compound of formula I obtained
into a pharmaceutically acceptable acid addition salt
thereof.
~. ..: , - .
Using the process according to the invention we
have prepared compounds of general formula I and pharma-
ceutically acceptable acid addition salts thereof in surpris-
ingly excellent yields.
The alkylation is preferably effected with an
', ,
~3-
, ~ . ... .

~ ~ 5~ S ~3
alkylating agent comprising a compound of formula
R - X (III)
[wherein Rl is as hereinbefore defined and X respresents
a chlorine, bromine or iodine atom or a group of formula
-0-SO2R3, (wherein R3 represents a methyl or 4-methyl-
phenyl group)]. -:.
. The alkylation is preferably effected in the
presence of a solvent, for example acetone, methanol,
dioxane or tetrahydrofuran~ advantageously in th2 presence
of a base, for ex~nple sodium hydroxide, potassium hydroxide
~, .
j or potassium tert.-butoxide, and conveniently at
temperatures rom ~C up to the boiling temperatures of . ::
the solvent used, for example at temperatures from 20 to
` 80C. .
When the alkylation is a methylatlon the reaction may
also be effected by heating the compo~md of formula II with
formaldehyde and formic acid, preferably at temperatures
from 80 to 100C.
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,
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5~3
It is surprising that the new process according to
the invention produces compounds of general formula l
(as hereinbefore defined) in such high yields since it
is known from the literature that in general no uniform
reaction product is obtained by alkylation of aminesO If
secondary amines are alkylated using an excess of an
appropriate alkylating agent, a mixture of the
corresponding tertiary organic amine and the corresponding
quaternary ammonium compound is usually obtained (see for
example Fieser & Fieser, Organic Chemistry~ page 229~ ; :
editor: Reinhold Publishing Corporation 1956 and Houben-
Weyl 11/I, page 24). If o-acylamino-benzylamines are
heated with acids~ in general 3,4-dihydro-quinazolines are
obtained and if o-acylamino-benzylamines are reacted with
formaldehyde, 1,2~3~4-tetrahydro-quinazolines are generally
formed (see for example Ao Weissenberger in Chemistry of
Heterocyclic Compounds 24/I~ pages 395 and 401 (1967).
The obtained compounds of general formula I may, if
desired, be subsequently converted into their acid ;~
addition salts, preferably their physiologically compatible
acid addition salt. Suitable acids for this purpose include
I for example hydrochloric acid, hydrobromic acid~ sulfuric
;~ ''.
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acid, phosphoric acid, lactic acid, cicric acid and malei.c
acid.
The ccmpounds of general II used as starting
materials may for example be obtained by reaction of the
corresponding benzylhalide with the appropria-te glycine
derivative~ '
The following Examples serve to illustrate the new
process according to the invention: ;~
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_xample 1
2-Benzoylamino-6-chloro-N-methyl-N-(morpholino-carbonyl~
methyl)-benzylamine
0.42 g (~.001 mol) of 2-benzoylamino-6-chloro-N-(morphol
ino-carbonyl-methyl)-benzylamine hydrochloride and 0.11 g
(0.002 mol) of potassium hydroxide were dissolved in 20 ml
of acetone and 0.28 g (0.002 mol) of methyl iodide ~ere
added at room temperature. The reaction mixture was left
to stand ~t room temperature for 15 hours. The precipit-
ated salts were then suction filtered and washed with ;
acetone. The acetone solution was evaporated and the
evaporation residue was dissolved in e~hyl acetate,
washed with water, dried over magnesium sulfate and
evaporated in vacuo, The residue was crystall~zed from
ether an~ 0,25 g ~62.2 % cf theory) of 2-benzoylamino 6-
chloro-N-methyl-N-(morpholino-carbonyl-methyl)-benzylamine
were obtained of m,p~ 122.5 to 123C.
Example 2
2-Benzoylamino-6-chloro-N-isopropyl-N-(morpholino-carbonyl-
methyl)-benzylamine _ -
~ .
I M,p,: 125 ~o 127C,
Prepared from 2-benzoylamino-6-chloro-N-(morpholino-
~ 7
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carbonyl-methyl)-benzylamine hydrochloride, isopropyl
iodide and potassium hydroxide analogously to Example 1.
Example 3
2-Benzo~lamino-4-chloro-N-meth~l-N-(isopropylamino-
carbonyl-methyl)-benzylamine
M.p. of the hydrochloride: 189 to 193 C (decomp.).
Prepared from 2-benzoylamino-4-chloro-N-(isopropylamino-
carbonyl-methyl~-benzylamine, methyl iodide and potassium
hydroxide analogously to Example 1.
xample 4
2-Benzoylamino 6-chloro-N-meth~l-N-(morpholino-carbonyl-
methy1~-benzylamine
2.12 g (0.0055 mol) of 2-benzoylamino-6-chloro-N-(morph- -
olino-carbonyl-methyl)-benzylamine (m.p.: 161 to 163 C),
S ml (0.012 mol) of 98% formic acid and 0.55 ml (0.0055
mol) of 30% aqueous formaldehyde solukion were heated for
6 hours on a steam bath. The mixture was evaporated to
dryness in vacua. The residue was dissolved in water and
the solution was again evaporated. After dissolving once
more in water~ the pH of the solution was adjusted to 9
and the oil which precipitated was extracted with ethyl
acetate. The organic extract was washed with water, dried
over magnesium sulfate and evaporated in vacuo. The
-8-
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., .: , . , , . . . , . :, , ,. , ~ ..

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residue was crystallized with ether, suction filtered
and the crystals were washed with ether. 1.50 g (67% of
theory) of the title compound were obtained having a m.p.
from 122.5 ~o 123 C.
Example 5
2-Benzoylamin_-6-chloro-N-meth~ morpholino-carbonyl-
methyl)-ben3~amine
1.25 g (0.0032 mol) of 2-benzoylamino-6-chloro-N-morphol-
ino-carbonyl-methyl)-benzylamine (m.p.: 161 to 163 C) and
o.6 g (0.00322 mol) of p-toluenesulfonic acid methyl
ester were refluxed in 30 ml of methanol for 6 hours.
~fter evaporation of the methanol in vacuo~ the residue
was dissolved in ethyl acetate and the solution obtained
was washed with water and 2N ammonia" The solution was
dried over magnesium sulfate and was then evaporated to
j dryness in vacuo. The residue was purified by chromat-
ography using a silica gel column with ethyl acetate as
eluent. The fractions containing the title compound were
evaporated in vacuo and the oil obtained was crystalli3ed
with ether. 0.42 g ~31% of theory~ of the title compound
of mOpO 122~5 to 123 C were obtained.
.,' . .
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.
. . . ,, : , . .

~ID 5~5~3
Examp].e 6
2-Benzoylamino-6-bromo-N~methyl-(morpholino-carbonyl-
methyl)-benzylamine
.
M.p.: 159 to 161C.
Prepared from 2-benæoylami.1o-6-bromo-N-(morpholino-
- carbonyl-methyl.)-benzylamine and forma].dehyde/formic acid
analogously to Example 4.
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