PREPARATION DES DERIVES DE BENZAMIDE

PROCESS FOR THE PREPARATION OF A BENZAMIDE DERIVATIVE

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
The invention provides a process for the preparation of
2-hydroxy-5-[1-hydroxy-2-[1-methyl-3-phenylpropyl))amino]ethyl}
benzamlde of the formula
( I )
<IMG>
and pharmaceutlcally acceptable acld addltion salts thereof which
comprises hydrogenating 2-hydroxy-5-{1-hydroxy-2-[(1-phenyl-but-
1-ene-3-ylldene)lmlno]ethyl}benzamlde of the formula
(V)
<IMG>
and, if desired, converting the compound of the formula I thus
obtained into a pharmaceutically acceptable acid addition salt.
The present invention also provides a compound of the formula V .

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 2-hydroxy-5-(1-
hydroxy-2-[(1-methyl-3-phenylpropyl)amlno]ethyl)beenzamlde of the
formula
( I )
<IMG>
and pharmaceutlcally acceptable acid addition salts thereof which
comprises hydrogenating 2-hydroxy-5[1-hydroxy-2-[1-phenyl-but-1-
ene-3-ylldene)lmlno]ethyl)benzamlde of the formula
( V )
<IMG>
and if desired converting the compound of the formula I thus
obtained into a pharmaceutlcaily acceptable acid addition salt.
2. A process according to claim 1 which comprises
carrying out the hydrogenation in the presence of a catalyst.
3. A process according to claim 2 which comprises
using a palladlum platinum or nlicke I catalyst or a mixture

thereof.
4. A process according to claim 1, which comprises
carrying out the reaction in the presence of an inert organic
solvent.
5. A process according to claim 4, which comprises
using an ether or alcohol as solvent.
6. A process according to claim 1, 2 or 3, which com-
prises carrying out the reaction at a temperature between 10°C
and 40°C and under a pressure of 1 to 10 atm.
7 A process according to claim 1, which comprises
using as starting material a compound of the formula V prepared
by reacting 2-hydroxy-5-(1-hydroxy-2-amlnoethyl)benzamide of the
formula
( I I )
<IMG>
with 1-phenyl but-1-ene-3-one of the formula
<IMG> (III)
8. A process according to claim 7, which comprises
carrying out the reaction in an inert organie solvent.
9. A process according to claim 8, which comprises
using an ether, alcohol or aromatie hydroearbon as solvent.
10. A process according to claim 7, which comprises
using 2-hydroxy-5-(1-hydroxy-2-amlnoethyl)benzamide of the for-
11

mula 11 prepared in situ by catalytic hydrogenation of 2-hydroxy-
5-[1-hydroxy-2-(N,N-dibenylamino)ethyl]benzamide of the formula
(VI) ,
<IMG>
reacting the compound of the formula II without isolation in situ
with the compound of the formula III and subjecting the compound
of the formula V thus obtained without isolation in situ, to
hydrogenation.
11. A process according to claim 7, which comprises
using 2-hydroxy-5-(1-hydroxy-2-aminoethyl)benzamide of the for-
mula 11 prepared in situ by catalytic hydrogenation of 2-hydroxy-
5-(N,N-dibenzylglycyl)benzamide of the formula
<IMG>
reacting the compound of the formula II without isolation in
situ, with the compound of the formula III and subjecting the
compound of the formula V thus formed without isolation In situ,
to hydrogenation.
12. 2-hydroxy-5-{1-hydroxy-2-[(1-phenyl-but-1-ene-32-
ylidene)imino]ethyl}benzamide of the formula
(V).
<IMG>
12

Description

~3~3~33~
Thls Inventlon relates ~o a process for the preparatlon
oF a benzamlde derlvatlve. More partlcularly, It Is concerned
~ h a new and Improved process For the preparatlon of 2-hydroxy-
5-~1-hydroxy-2~ methyl-3-phenylpropyl)-amlno]ethyl}benzamlde
and pharmaceutlcally acceptable acld addltlon salts thereof.
It Is known that 2-hydroxy-5-{1-hydroxy-2-~(1-methyl-3-
phenylpropyl)-amlno]ethyl~benzamlde Is a,useful and wlde spread
alpha- and beta-blocklng hypotenslve agent.
In the prlor art a number of procedures are dlsclosed
for the preparatlon of 2-hydroxy-5-C1-hydroxy-2-[(1-methyi-3-
phenylpropyl)amlno]ethyl}benzamlde. Accordlng to DOS No.
2,032,642, 2-hydroxy-5-acetylbenzamlde Is bromlnated, the ~)-bro-
moacetyl derlvatl~e thus obtalned Is reacted wlth N-b~nzyl-N-(1-
methyl-3-phenylpropyl)amlne and the ~eto group of the 2-hydroxy-
5-~2-~N-benzy1-N-(1-methyl-3-phenyipropyl)-amlno] acetyl}benz-
amlde Is reduced by catalytlc hydrogenatlon while the protectlng
N-benzyl group Is cleaved to ylelci 2-hydroxy-5-{1-hydroxy-2-r~1-
methyl-3-phenylpropyl)amlnoie-thyl} benzamlde.
The drawback of thls process Is that the end-product Is
obtalned by means of a synthesls comprlslng many steps and In low
yields. Moreover, the N-benzyl-N~(1-methyl-3-phenylpropyl)amine
component can be produced only In the multlstep synthesls In a
complIcated manner, too.
Accordlng to another process dlsclosed In DOS No.
2,032,642~ 2-hydroxy-5-(bromoacetyl)benzamlde Is reacted with
N,N-dlbenzylamlne and the 2-hydroxy-5-(N,N-dlbenzylglycyl)-benza--
; mlde of the formula
36
-- 1 -- 3
, ~

~ ~ 3~
CONrl2 / C~12 ~ (IV)
llO ~ CIT, - N ~
obtalned Is reac-ted wlth 1-phenyl-3-butanone under reduclng con-
dltlons. The ylelds achleved are medlum. A further dlsadvantage
vF thls method resldes In the fact that 1-phenyl-3-butanone Is
not avallable on Industrlal scale and In the prlor art no econom-
lcal Industrlal scale rrlanu~acturlng process o~ the sald compound
Is dlsclosed.
Accordlng to a further method of sald DOS 5-(2-am1no-
12-hydroxyethyl)sallcylamlde Is reacted wlth 1-phenyl-3-butanone
In ethanoll~ solutlon under reduclng condltlons t~ ~Ive the
deslred compound 2-hydroxy-5--C~-hydroxy-2-~(1-methyl-3-phenyl-
propyl)amlno]ethyl}benzam1de.
In the correspondln~ example, however, no y~eld ~s
glven. A dra~back of thls method Is 9 ~S It was already mentloned
aboYe, that 1-phenyl-3-butanone startlng materlal Is not avall-
able on Industrlal scale.
2~ In Belgian patent No. 840,7799 and DOS No. 2,616,403 a
process For the preparatlon and separatlon of dlasteroisomers of
Z-hydroxy-5-C1-hydroxy-2-~1-methyl-3-phenylpropyl)amlno] ethyl}
benzamlde Is dlsclosed. ~n the me~ho~s described hereln as a
result of the formatlon of the chlral centrum the number of r-eac-
tlon steps Is Increased, and the total yleld of the synthesls Is
; rather low.
Accordlng to the general formulae of ~lungarlan patent
No. 165,291, 2-hydroxy-5-{1-hydroxy-2-~(1-methyl-3-phenylproPyl)
amlno]ethyl~benza~lde rnay be prepared by condenslng 2-hydroxy-5-
glyoxylylbenzolc acld ester wlth 1-phenyl-3-butylamlne and sub-

3~
Jectlng the SchifF base thus obtalned to catalytic hydro~enatlon.In the patent speclflca-~lon, ho~ever, no exampJe is dlsclosed For
the pr~paratlon oF 2-hydrvxy-~-C1-hydroxy-2-~(1-methyl-3-phenyl-
propyl)amino~ethyl3benzamlde.
It Is the obJect of the present Inventlon to elaborate
a proces~ for the preparatlon o-F 2-hydroxy-5-{1-hydro~y-2-[(1-
methyl-3-phenylpropyl)amlno]ethyl}benzamlde whlch ellmlnates the
above drawbacks of the Icnown methods, provldes hlgher ylelds, Is
readlly feaslble on Industrlal scale pro~uctlon and uses easlly
avallable startlng materlals.
It has been found that 2-hydroxy-5C1-hydroxy-2-
~
methyl-3-phenylpropyl)amlno]ethyl}benzamlde of the formula
('ONII
16 \ 2 . ( r )
ElO ~ Cll- Cl[
011 Nl-l - Cll
C112 - Cl12 - ~
may be prepared In a more slmple and economlcal manner from ~-
hydroxy-~-[1-hydroxy-2-[(1-phenyl-but-1-ene-3-ylldene)-lmlno3
ethyl~benzamlde of the formuia
CON~12
llO ~ 3 (V)
Oil N = C
\ Cll = C~{
3~ ~ ~
Accordlng to the present Inventlon there 19 provlded a
process for the preparatlon of 2-hydroxy-5-{1-hydroxy-2-~(1-
methyl-3-phenylpropyl)amlno]ethyl}benzamlde of the formula I and
3~ pharmaceutlcally acceptable acld addltlon salts thereo~ whlch
comprlses hydrogenatlng 2-hydroxy-5-C1-hydroxy-2-~(1-phenyl-but-
~ .....

3~9~3~
1-ene-3-ylldene)amlno]ethyl}benzamlde of the Formula V and, IF
deslred, convertlng the compound o~ the formula ~thus obtalned
Into a pharmaceutlcally acceptable acld addi-tlon s~lt.
The reduction oF the Schlff base of the formula ~may
be carrled out by catalytlc hydrogenatlon. As cataiyst
preferably paliadlum, platlnum, nlckel or an Adams catalyst may
be used. The catalyst may also be applled on a carrler (e.g.
charcoal, barlum sulfate). Hydrogenatlon may be carrled out at a
10 temperature of about 20-30C, and under a pressure of 1-10 atm.,
preferably 2-4 atm. One may partlcularly advantageously work at
25C and under a pressure of 3 atm. The reductlon may be carrled
out In an Inert organic soivent. As reactlon medlum preFerbly an
ether (e.g. dlethyl ether, dloxane or tetrahydrofurane~ or an
alcohol le.g. methanol or ethanol), partlcularly tetrahydroFurane
may be used. In the course of the reactlon two equlvalents of
hydrogen are consumed and both the azome-thlne bond and carbon-
carbon double bond are saturated. The reactlon may be
accomplIshed In the presence of a small amoun-t of an or0anlc acld
(e.g. glaclai acetlc acld). The ylelds achleved are almost
theore-tlc.
The reactlon mlxture may be worked up by methods known
~ se. One may preferably proceed by fllterlng off the catalyst
and evaporatlng the flltrate. The hydrochlorlde may be Isolated
by addlng anhydrous ethanollc hydrogen chlorlde or a mixture of
concentrated hydrochlorlc acld and ethanol to the hydrogenated
flltrate.
The startlng materlal of the Formula V Is a new com-
pound and may be prepared by reactlng 2-hydroxy-5-(1-hydroxy-2-
amlnoethyl)benzamlde of the formula

3~3~
CON~-I
2 ( II )
~10 -- _ CH - CH2
OH NH2
wlth 1-phenyl-but-1-ene-3-one of the formula
~ ~ ( III),
W CH = C~l - COC113
The reactlon may be carrled out In an Inert organlc solvent. As
reactlon medlum preFerably ~n e-ther ~e.~. dlethyl ether, dloxane
or tetrahydrofurane), alcohol (e.g. methanol or etharlol) or an
aromatlc hydrocarbon (e.g. benzene, toluene or xylene), partlcu-
larly tetrahydrofurane may be used. The reactlon may be accom-
pllshed at a temperature between ~5-100C, preferably at a tem-
perature of about 40C. The reactlon may optlonally be carrled
out In the presence of a base (e.g. trlethyl amlne or morpho-
llne).
The compound of the formula ~ thus obtalned may either
be Isolated or subJected to catalytlc hydrogenatlon In sltu wlth-
out Isolatlon.
Accordlng to a form of realIzatlon of the process ofthe present Inventlon the compound of the formula 11 prepared by
catalytlc hydrogenatlon of the compound of the formula
llO ~ Cll - CH2 - N ~ (VI)
0~ C~l2 -
-- 5 --
,~ .

3~3
Is used. One may wor~ preferably by subJectlng a compound of the
Formul~ Vl to catnlYtlc hydrogenatlon, reactlng the compound of
the formula 1~ thus formed In sltu wlth the compound of the for-
__
mula 1~ and hydrogenatlng the compound of the formula V thusformed wlthout Isoia~lon.
Accordlng to a further form of reallzatlon oF -the pro-
cess of the present Inventlon the compound of the formula 1~ pre-
pared by ca~alytlc hydrogenatlon of the compound of the Formula
IV Is used. One may proceed preFerably by subJectlng the com-
pound of the iormula IV to catalytlc hydrogenatlon, reactlng the
compound of the formula IV to catalytlc hydrogenatlon, reactlng
the compound of the formula 1~ thus Formed In sltu wlth a corn-
pound of the Formula ~ and hydrogenatlng the compound of the
formula V thus formed wlthout Isolatlon.
The two Iatter forms of reallzatlon of the process of
the present Inventlon may be carrled out preferably at an ele-
vated temperature, preFerably at 50-70C and under a pressure
between 1 and 100 atm., preferably under a pressure of about 50
atm. The reactlon may be carried out In an Inert organlc
solvent. As reactlon medlum preferably an alcohol (e.g. methanol
or ethanol) may be used. The reactlon mlxture may also contaln
an acld (e.g. glaclal acetlc acld). As catalyst e.g. pailadium,
platlnum, nlckel or Adams catalyst may be used. The catalyst may
be applled onto a carrler, e.~. charcoal, barlum sulfate, etc.,
If deslred.
The maJor advantage of the process oF the present
Inventlon Is that -the s-tartlng materlals ~sed for the preparatlon
of the compound of the formula V may be prepared from materlals
(e.g. benzal acetone) readlly feaslble and economlca~ on indus-
trlal scale, ~oo and the yields are hlgh.
3~ Wlthout llmltlng the scope of the inventlon by theoret-
lcal conslderatlons we presume that thls Is due to the Fact tha-t

~3~3~
because oF conJugatlon -the keto group oF 1-phenyl-bu-t-1-ene-3-one
(benzal acetone) u~ed In the process of the present Inventlon Is
more reactlYe than the keto group of 1-phenyl-butan-3-one applled
In the process dlsclosed ~n DOS No. 2,03Z,642. For thls reason
the compound of the formula lll reacts wlth the 2-hydroxy-5-(1-
hydroxy-~-amlno-ethyl)-benzamlde of the formula ll to give the
correspondlng 2-hydroxy-5-[1-hydroxy-Z-~(1-phenyl-but-1-ene-3-
ylldene)Imlno~ethyl)-benzamlde much more easlly than the corre-
spondlng Intermedlate Is formed In the process descrlbed In DOS
10 No. 2,032,6~Z, namely 2-hydroxy-5 r 1-hydroxy-2-[(1-phenyl-but-3-
ylldene)lmldo]ethyl~benzamlde or 2-hydroxy-5-C1-keto-2-[(1-
phenyi-but-3-ylldene)-Imlno]ethyl}benzamlde.
Further detalls of the process of the Inventlon are to
be found In the followlng Examples wlthout llmltlng the scope of
protectlon by the sald Examples.
Example 1
Preparatlon of 2-hydroxy-5-{1-hydroxy-2-[(1-phenyl-but-1-ene-3-
ylldene)amlno]ethyl~benzamlde
2.30 9 (10 milllmoles) of 2-hydroxy-5-(1-hydroxy-2-
amlnoethyl)benzamld0 hydrochlorIde and 1.46 9 (10 mllllmoles) of
25 1-phenyl-~ut-1-ene-3-one are admlxed wlth 10 ml of tetrahydrofu-
rane whereupon under further stlrrln~ and Ice-coolIng 1.20 ~l of
trlethyl amlne are added dropwlse at a temperature of 10-15C.
The addltlon havlng been completed the reactlon mlxture Is
stlrred at room temperature for further 5 hours and the preclpl-
tated trlethyl amlne hydrochlorIde Is filtered of-F. From the
; flltrate the 2-hydroxy-5-{1-hydroxy-2-~ phenyl-but-1-ene-3~yll-
dene)Imlno~-ethyl}benzamlde Is Isolated by column chromatography
on slllca gel. Thus 1.56 g of the deslred compound are obtalned,
yleld 48%, m.p.: 142-146C.
~.'

Exam~le Z
Preparatlon of 2-hydroxy-5-~1-hy~roxy-2-[~l-phenyl-but-1-ene-3-
ylldene)lmlno]ethyl}benzamlde
2.30 ~ ~10 mllllmoies) of 2-hydroxy-~-(1-hydroxy-2-
amlnoe-thyl)benzamlde hydrochlorlde and 1.46 9 (10 mllllmoles) of
1-phenyl-but-1-ene-3-one are admlxed wlth 10 ml of tetrahydroFu~
ran, whereupon under Further stlrrlng and Ice-coollng 4 ml oF
morpholIne are added dropwlse at a temperature oF 10-15C. The
reactlon mlxture Is stlrred at room temperature for a Further
perlod of 5 hours, the preclpltated morphollne hydrochlorlde Is
flltered o~f and the FlItrate Is heated to bolllng for 3 hours.
From the flltrate the deslred compound Is Isola-ted by column
chromatography on slllca gel. Thus 2.05 9 of the deslred com-
pound are obtained, yleld 63%, M.p.: 142-145C.
Example 3
Preparatlon of 2-hydroxy-5-{1-hydroxy-2-C~1-methyl-3-phenyl-
pro~yl)amlnoiethyl}benzamlde hydrochlorlde
3.24 9 ~10 mlllimoles) of 2-hydroxy-5-[1-hydroxy-2-~(1-
phenyl-but-l-ene-3-ylldene)lmlno~iethyl}benzamlde prepared accord-
Ing to Example 1 or 2 are dlssolved In 25 ml of te-trahydro~uran,
~hereupon 0.5 ~ of a 10~ paliadlum-on-charcoal catalyst are added
and the mixture Is hydrogenated at a temperature of 25C under a
pressure oF 3 atm. The reductlon havlng been termlnated the cat-
alyst Is Flltered ofF and to the flltrate 5 ml of ethanol con-
talnln~ 20% of hy~lrochlorlc acld are added. The preclpltatedwhlte crystals are flItered off and washed wl-th ethanol. Thus
3.46 9 of the deslred compound are obtalned, yleld 95~, m.p.:
188-189C.
.

~3~
Exam~e 4
Preparatlon of 2 hydroxy-5-t1-hydroxy-2-[(1-methyl-3-phenyl-
propyl)amlno]ethyl~benzamlde hydrochlorlde
To a solutlon of 3.74 g (10 mllllmoles) of 2-hydroxy-5-
(N7N-dlbenzylglycyl)benzamlde, 1.46 g (10 ml~llmoies) of 1-
phenyl-but-1-ene-3-one and 50 ml of methanol 1.0 ml of glaclal
acetlc acld, 1.0 9 of a 10% pailadlum-on-charcoal catalyst and
0.1 g of platlnum oxlde (Adams catalyst) are added. The reactlon
mlxture Is hydrogenated at a temperature o-F 60C and under a
pressure of 50 atm. The catalyst Is flltered off and the fll-
trate Is evaporated to a small volume. T~ the resldue 3 ml of
propanol saturated wlth hydrogen chlorlde and 5 ml of ethyl
acetate are added. On standlng crystals preclplta-te whlch are
flltered off and washed. Thus 2.62 g of the deslred compound are
obtalned, yleld: 72%, m.p.: 187-190C.
Example 5
Preparation of 2-hydroxy-5-{1-hydroxy-2-~(1-methyl-3-phenyl-
propyl)amlno]ethyl~benzamlde hydrochlorlde
l~o a solutlon of 3.7~ g (10 milllmoles) of 2-hydroxy-5-
25 ~I-hydroxy-2-(dlbenzylamlno)ethyl]benzamlde nnd 1.~ 9 (10 mll-
llmoles) of 1-phenyl-but-1-ene-3-one ln 50 ml of methanol 2.0 ml
of glaclal acetlc acld, I.O g of a 10% palladlum-on-charcoal cat-
alyst and 0.1 9 of platlnum oxlde (Adams catalyst) are added and
the reactlon mlxture Is hydro~enated at a temperature of 60C and
under a pressure of 50 atm. The reactlon mlx-ture Is worked up
and the produc-t Isolated accordlng to Example ~. Thus 2.77 9 of
the deslred product are obtalned, yleld 76%, m.p.: 18fl-189C.
~,: