SYNTHESE D'ACYLAMINO-2 BENZYLAMINES

PROCESS FOR THE PREPARATION OF 2-ACYLAMINO-BENZYLAMINES

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
This invention relates to a new process for the
preparation of 2-acylamino - benzylamines having
valuable pharmacological properties and/or being
intermediates for the preparations of valuable
pharmacologically active compounds. The new process
comprises the reaction of the corresponding
benzoxazines with appropriate primary or secondary
amino compounds. Examples of the preparation of
certain 2-acylamino - benzylamines by means of the new
process are given. The benzoxazines compounds used as
starting materials are also new and a process for thier
preparation is described and exemplified.

Revendications

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 a hydrogen
or bromine atom, R2 represents a hydrogen atom or an alkyl group containing
from 1 to 3 carbon atoms; R3 represents a cyclohexyl, hydroxycyclohexyl,
isopropylaminocarbonylmethyl or morpholinocarbonylmethyl group; and R4
represents benzoyl group) and pharmaceutically acceptable acid addition
salts thereof which comprises reacting a compound of formula
<IMG> (II)
(wherein Hal and R1 are as hereinbefore defined and R4' represents a phenyl
group) with a compound of formula
<IMG> (III)
(wherein R2 and R3 are as hereinbefore defined) and if desired subsequently
converting the compound of formula I thus obtained into a pharmaceutically
acceptable acid addition salt thereof.
2. A process as claimed in claim 1 wherein the group R4' in the com-
pound of formula II used is a phenyl, 2-chlorophenyl or 4-methylphenyl group.

3. A process as claimed in claim 1 or claim 2 wherein the reaction
is effected in the presence of a solvent.
4. A process as claimed in claim 1 or claim 2 wherein the reaction
is effected in the presence of an excess of the amine of formula III used.
5. A process as claimed in claim 1 or claim 2 wherein the reaction
is effected at temperatures from 100 to 200°C.
6. Compounds of general formula 1 as defined in claim 1 and
pharmaceutically acceptable acid addition salts thereof whenever prepared
by a process as claimed in claim 1 or by an obvious equivalent thereof.
7. A process according to claim 1 in which 2-benzoyl-N-cyclohexyl-
3,5-dibromo-N-methylbenzylamine and its hydrochloride is prepared by reacting
6,8-dibromo-2-phenyl-4H-3,1-benzoxazine hydrobromide with excess N-methyl-
cyclohexylamine and when the hydrochloride is required reacting the base
so obtained with hydrogen chloride.
8. A process according to claim 1 in which 2-benzoylamino-6-chloro-
N-methyl-N-(morpholinocarbonylmethyl)benzylamine is prepared by reacting
5-chloro-2-phenyl-4H-3,1-benzoxazine with sarcosine morpholide.
9. A process according to claim 1 in which 2-benzoylamino-6-chloro-
N-isopropyl-N-(morpholinocarbonylmethyl)benzylamine is prepared by reacting
5-chloro-2-phenyl-4H-3,1-benzoxazine with N-isopropylglycine morpholide.
10. A process according to claim 1 in which 2-benzoylamino-4-chloro-
N-methyl-N-(isopropylaminocarbonylmethyl)benzylamine is prepared by reacting
7-chloro-2-phenyl-4H-3,1-benzoxazine with sarcosine isopropylamide.
11. A process according to claim 1 in which 2-benzoylamino-6-bromo-
11

N-(morpholinocarbonylmethyl)benzylamine is prepared by reacting 5-bromo-2-
phenyl-4H-3,1-benzoxazine with sarcosine morpholide.
12. A process according to claim 1 in which 2-benzoylamino-3,5-
dibromo-N-methyl-N-(morpholinocarbonylmethyl)benzylamine is prepared by
reacting 6,8-dibromo-2-phenyl-4H-3,1-benzoxazine with sarcosine morpholide.
13. 2-Benzoylamino-6-chloro-N-methyl-N-(morpholinocarbonylmethyl)-
benzylamine whenever prepared by the process of claim 8 or by an obvious
chemical equivalent thereof.
12

Description

59~
This invention relates to a new process for the
preparation of 2-acylamino - benzylamine derivatives
having valuable pharmacological activity and/or being
intermediates for the preparation of valuable
pharmacologically active compounds.
The preparation of 2-amino-benzylamines by
reacting the corresponding 4H-3, 1-benzoxazines with
amines is known from the literature (see for example R. C.
Elderfield "Heterocyclic Compour.ds"~ Vol. 6, page 574).
According to the present invention there is
provided a process for the preparation of' compounds of
general formula
.
~ R3
,: ~H R~
1 Rl ,
(wherein Hal represents a chlorine or bromine atom, Rl
.. : .
"' '' ~
" ' ,
, - 2 -
, , ' ' .

5~
represents a hydrogen or bromine atom; R2 represents a hydrogen atom or
an alkyl group containing from 1 to 3 carbon atoms; R3 represents a
cyclohexyl, hydroxycyclohexyl, isopropylaminocarbonylmethyl or
morpholinocarbonylmethyl group, and R4 represents a benzoyl group) and
pharmaceu~ically acceptable acid addition salts thereof which comprises
reacting a compound of formula
Hal
~ ~ CH2\ (II)
R~ ~C-R4'
Cwherein Hal and Rl are as hereinbefore defined and R4' represents a
phenyl group) with a compound of formula
/R2
H N (III)
Cwherein R2 and R3 are as hereinbefore defined) and if desired subsequently
converting the compound of formula I thus obtained into a pharmaceutically
acceptable acid addition salt thereof, ~ :
The present invention also relates to compounds of general ~-
formula I as previously defined and pharmaceutically acceptable acid
addition salts thereof whenever prepared by a process as described above.
.'",',:'
. .. ...
.. ... .
, ~. . .

~L~5(3 5~ :
The group R4' is the compound of formula II may
for example represent a phenyl, 2-chlorophenyl or 4-methyl :~
phenyl groupO ~
Using the process according to the invention we .
have prepared compounds of general formula I and acid
addition salts thereof in excellent yields.
The reaction is conveniently carr1ed out in the :-
presence of a solvent, for example tetraline, or in the
: presence of an excess of~the amine of formula III used, at
temperatures from 100 to 200 C, preferably, however, at
temperatures from 130 to 180 C. The reaction may, however,
also be carried out in the absence of a solvent.
The compounds of general formula I thereby
obtained may~ if desired, be subsequently converted into
--
: their acid addition salts, preferably their physiologically
~ .
,' ~'
''. ' , . ' .
. .
.,
: i:
., . .: : . , '.
~. . . .

~L~5054~ ~
compatib.le 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 coinpounds of general for.~ul~
Hal,~ R 7
Rl \ N~ 4 (II )
(wherein Hal. represents a chlorine or bromine atom, R
represellts a hydrogen, chlorine or bromine atom and ~4'
represents an aryl group, for example a pheny].~ 2-
chlorophenyl or 4;methyl.phenyl ~roup).and acid ~ddition
~salts thereof are new compounds and constitute a furtller ; .
f~ature of the present invention. They may be prepared . .
,
~ according to the following process:
', Dehydration of a compound of ~ormula
Ua}~cH2--OH (IV)
R NH R4
', , ' ' ~ ,.
: - 5 -
,. .
, ' , .
. .. ., , . .. , ......................... , . , .,,,, . .. :, .. ... . . .. ... . . .. .
~,, . ,., ." .,. -,; ,,., , . . , ., .. : , ,,. .,, .. , , .. , . , ., .. ~,; ,.".. ,, :. . . . .

~ L~5~544
(wherein ~lal and Rl are as hereinbeforedefined ~nd R4
represents an aromatic organic acyl group).
The dehydration is conveniently effected by mea~s of
a dehydrating agent, advantageouc].y a mineral acid, for
example hydrochloric acid, hydrobromic acid, sulph~ric
acid or phosphoric acid `
The reaction is preferably carried out in the presen-
ce of a solvent,for example ether, tetrahydrofuran or
dio~ane conveniently at temperatures frorn.0 to 50C,
preferablyj however, at temperatures frorn 15 to 25C.
- The benzyl of general formula IV used as starting
materials may.for example be obtained by reaction of the
corresponding ~ -amino~benzyl alcohols (which rnay be
obtained by reduction of the corresponding benzaldehydes
with ~sodium borohydride) with appropriate aromatic acid
halides ln pyridlne and subsequent alkaline saponifica-
tion of the esters formed.
s
.s
6 ~ :
,; i :
~~,
,, ' ' i ~
, , ': ' . . , ' . '. ': :
, , , , , , , : ~ ,, .:.

:
~5054~
The following Examples serve to illustrate the
preparation of compounds of general formula I and II
as h~reln dcfined, and acid addition salts thereof, I :
in accordance with the present invention: <
Examl~l.e A
.
6~Di.~ro~o - 2-~heny]-4H-3~ l-~enzoxaæine
.. ..
600 ml of absolute ether were added to 11 g of 2
benzoylamino-3,5-dibromo benzyl alcohol. Gaseous `~
hydrogen bromide was introduced into the mixture for
~: 30 minutes whilst stirring. 6,8-Dibromo-2-phenyl- ~ .
: . 3,1-beDzoxazine hydrobromide precipitated out of the
: starting solution. After stirring for 6 hours, the
precipitate was suction filtered and recrystalized from .. ...
absolute ethanol
~M.p. of the~hydrobromide: 218 to 221C. `
:~ 5-Chioro-2-phenyl-4H-3,1-benzoxazine
M.p.: 88.5 to 89. 5C
.
I - 7 ~ ~
, .
'', . ~"''':`'. ' ',
. , ~ .:'. '-.
, , ~, . .
. ' ' . ~
':

~LED5~
Prepared from 2-benzoylamino-6-chloro-benzyl alcohol analogously to Example
A.
Example 1
2-Benzoylamino-N-cyclohex~1-3~5-dibromo-N-methyl-benzylamine
11.2 g (0.025 mol) of 6.8-dibromo-2-phenyl-4H-3,1-benzoxazine
hydrobromide were refluxed with 17.0 g (0.15 mol) of N-methyl-cyclohexylamine
for 1.5 hours. Subsequently, the reaction mixture was mixed with 2N sodium
hydroxide solution and extracted several times with ether and the organic
layer was then dried over sodium sulfate and evaporated to dryness. The
residue was dissolved in absolute ethanol and ether and the solution was
acidified with ethanolic hydrochloric acid, whereby the 2-benzoylamino-N-
cyclohexyl-3,5-dibromo-N-methyl-benzylamine hydrochloride crystallized ou~.
Yield: 12.1 g (93.7~ of theory),
m.p.: 270 to 272 C (decomp.).
Example 2
2=Benzoylamino-6-chloro-N-methyl-N-(morpholino-carbonyl-methyl)-benzylamine
M.p.: 122.5 to 123 C.
Prepared from 5-chloro-2-phenyl-4H-3,1-benzoxazine and sarcosine morpholide
analogously to Example 1.
Example 3
2-Benzoy_amino-6-chloro~N-isopropyl-N-(mor~holino=carbo~yl-methyl)-
benzylamine
M.p.: 125 to 127 C.
Prepared from 5-chloro-2-phenyl-4H-3,1-benzoxazine and N-isopropyl-glycine
morpholide analogously to Example 1.
Example 4
2-Benzoy mino-4-chloro-N-methyl-N-(isopro~ylamino-c_rbonyl~methyl)-
benzylamine -~
M.p.: 140 to 142 C.
Prepared from 7-chloro-2-phenyl 4H-3,1-benzoxazine and sarcosine isopropyl-
amide analogously to Example 1.
..
- 8 -
-. , , , . . , .. .. :. , : , . :
: .. : . . . : :
, . , . :. , ., . .. . : . ...

~5~
Example 5
-Benzoylamino-6-bromo-N-(morpholino-carbonyl-meth~)benzylamine
M.P.: 159 to 161 C.
Prepared from 5-bromo-2-phenyl-4H-3,1-benzoxazine and sarcosine morpholide
analogously to Example 1.
Example 6
2-Benzoylamino-3,5-dibromo-N-methyl-N-(morpholino-carbonyl-methyl)-
benzylamine
M.p.: 164 to 166 C.
10 Prepared from 6,8 dibromo-2-phenyl-4H-3,1-benzoxazine and sarcosine morpho-
lide analogouslyto Example 1.
_ g - '~.
.'.