PROPANOL DERIVATIVES

DERIVES DU PROPANOL

English Abstract

ABSTRACT OF THE DISCLOSURE
The invention relates to novel propanol derivatives of the
formula:
<IMG>
(I)
wherein R1 represents a hydrogen or halogen atom, a hydroxy or trifluoro-
methyl group or an alkyl or alkoxy group with I to 4 carbon atoms; and
R2 represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms
or a benzyl group or a pharmaceutically acceptable acid addition salt
thereof, and to processes for their preparation. The novel compounds
possess sympathicomimetic properties and are potentially useful as cardiac
and circulation agents. In particular the novel compounds possess a blood
pressure increasing activity. The novel compounds, may, moreover serve as
intermediates in the preparation of other physiologically active compounds.
Processes for the production of the novel compounds are described and
examples of certain of the novel compounds are given. Pharmaceutical
compositions containing the novel compounds are described and exemplified.

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 a compound of the formula:
<IMG> (I)
wherein R1 represents a hydrogen or halogen atom, a hydroxy or trifluoro-
methyl group or an alkyl or alkoxy group with 1 to 4 carbon atoms; and
R2 represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or
a benzyl group or a pharmaceutically acceptable acid addition salt thereof,
which comprises either: (a) reducing a compound of the formula:
<IMG> (II)
wherein R1 is as defined above, R2' represents the radical R2 or an acyl
group with 1 to 4 carbon atoms or a benzoyl group, and R3 represents an
optionally substituted alkoxy group and where R2' is an acyl group as
hereinbefore defined, deacylating the product so obtained; (b) or subjec-
ting a compound of the formula:-
<IMG> (III)
wherein R4 represents a hydrogen atom or a group removable by ether
splitting, hydrolysis or by hydrogenolysis, R5 represents the radical R1
39

as defined above or the group -OR7 in which R7 represents a group
removable by ether splitting, hydrolysis or hydrogenolysis, and R6
represents the radical R2 or a group removable by hydrogenolysis, with
the proviso that at least one of R4, R6 and R7 represents a removable
protecting group: (c) or reducing a compound of the formula:-
<IMG> (IV)
wherein R1 is as defined above; (d) or for the preparation of a compound of
formula I in which R2 represents an alkyl group with 1 to 4 carbon atoms
or a benzyl group, by alkylating or benzylating a compound of the formula:-
<IMG> (V)
wherein R1 is as defined above, either directly or by reaction with the
appropriate aldehyde with 1 to 4 carbon atoms or benzaldehyde followed by
reduction, (e) or for the preparation of a compound of formula I in which
R2 represents an alkyl group of 1 to 4 carbon atoms or a benzyl group,
reducing a compound of the formula:-
<IMG> (VII)
wherein R1 is as defined above and R8 represents a hydrogen atom, an alkyl
group with 1 to 3 carbon atoms or a phenyl group, and wherein any of steps
(a) to (e) may be followed by the additional step of converting a base of

formula I obtained into a corresponding pharmaceutically acceptable acid
addition salt.
2. A compound of the formula:
<IMG> (I)
wherein R1 represents a hydrogen or halogen atom, a hydroxy or trifluoro-
methyl group or an alkyl or alkoxy group with 1 to 4 carbon atoms; and
R2 represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or
a benzyl group or a pharmaceutically acceptable acid addition salt thereof,
whenever prepared by the process of Claim 1 or by an obvious chemical
equivalent thereof.
3. A process according to Claim 1 which comprises reducing a
compound of the formula:
<IMG> (II)
wherein R1 is as defined in Claim 1, R2' represents the radical R2 or an
acyl group with 1 to 4 carbon atoms or a benzoyl group, and R3 represents
an optionally substituted alkoxy group with a complex hydride and, where
a compound is obtained in which R2' represents an acyl group, deacylating
said compound whereby a compound of formula I is obtained.
4. A process as claimed in Claim 3 wherein the deacylation is
effected by treatment with hydrochloric acid.
5. A process according to Claim 3 in which the complex hydride is
41

lithium aluminium hydride, sodium di-(methoxyethoxy)aluminium hydride,
lithium borohydride, sodium borohydride or calcium borohydride.
6. A process as claimed in Claim 3 wherein the complex hydride
comprises lithium aluminium hydride.
7. A process as claimed in Claim 3 wherein the complex hydride
comprises sodium di(methoxyethoxy)aluminium hydride.
8. A process as claimed in Claim 3 wherein the complex hydride
comprises lithium borohydride, sodium borohydride or calcium borohydride.
9. A process according to Claim 1 which comprises subjecting a
compound of the formula:-
<IMG> (III)
wherein R4 represents a hydrogen atom or a group removable by ether
splitting, hydrolysis or hydrogenolysis, R5 and R6 are as defined in Claim
1 with the proviso that at least one of R4, R6 and R7 represents a remo-
vable protecting group as defined above, to ether splitting, hydrolysis
or hydrogenolysis whereby the said compound of formula III is converted
into a compound of formula I.
10. A process as claimed in Claim 9 wherein a compound of formula
III is used in which R4 and/or R7, where present, represents an alkyl,
benzyl, or acyl group, said compound being subjected to ether cleavage,
hydrogenolysis or hydrolysis.
11. A process as claimed in Claim 9 wherein a compound of formula
III is used in which R4 and/or R7 represents a methyl or benzyl group,
42

said compound being subjected to ether cleavage or hydrogenolysis.
12. A process as claimed in Claim 9 wherein the hydrolysis is
effected by the use of an aqueous acid or base.
13. A process as claimed in Claim 9 wherein the hydrogenolysis is
effected in the presence of platinum, palladium or Raney nickel as
hydrogenation catalyst.
14. A process as claimed in Claim 9 wherein the ether splitting or
hydrolysis is effected by the use of hydrobromic acid, hydrochloric acid,
boron trifluoride etherate, boron tribromide or aluminium chloride.
15. A process according to Claim 1 which comprises reducing a
compound of the formula:-
<IMG> (IV)
(wherein R1 is as defined in Claim 1) whereby a compound of formula I is
obtained.
16. A process as claimed in Claim 15 wherein the reduction is
effected by catalytic hydrogenation.
17. A process as claimed in Claim 16 wherein the catalytic hydro-
genation is effected in the presence of platinum,palladium or Raney nickel
as hydrogenation catalyst.
18. A process according to Claim 1, wherein R2 represents an alkyl
group with 1 - 4 carbon atoms or a benzyl group, which comprises alkylating
a compound of the formula:-
43

<IMG>
(V)
either directly or by reaction with the appropriate aldehyde with 1 - 4
carbon atoms or benzaldehyde followed by reduction, wherein R1 is as
defined in Claim 1 whereby a compound of formula I, wherein R2 represents
an alkyl group with 1 to 4 carbon atoms or a benzyl group, is obtained.
19. A process according to Claim 1, wherein R? represents an alkyl
group with 1 - 4 carbon atoms or a benzyl group, which comprises reducing
a compound of the formula:-
<IMG> (VII)
wherein R1 is as defined in Claim 1 and R8 represents a hydrogen atom, an
alkyl group with 1 - 3 carbon atoms or a phenyl group whereby a compound
of formula I, wherein R2 represents an alkyl group with 1 - 4 carbon atoms
or a benzyl group, is obtained.
20. A process as claimed in Claim 19 wherein the reduction is
effected by the use of a complex hydride.
21. A process as claimed in Claim 20 wherein the complex hydride
comprises lithium aluminium hydride or sodium di-(methoxyethoxy)aluminium
hydride.
44

22. A process as claimed in any of Claims 19 to 21 wherein the
compound of formula VII is first prepared by acylating a compound to the
formula:-
<IMG> V
wherein R1 is as defined in Claim 19, whereby a compound of formula VII as
defined in Claim 19 is obtained.
23. A process according to Claim 1 in which R1 (or R5) represents a
hydrogen, fluorine, chlorine or bromine atom or a hydroxy, methyl, methoxy
or trifluoromethyl group and R2 (or R6) represents a hydrogen atom or a
methyl, ethyl or benzyl group.
24. A compound as claimed in Claim 2 wherein R1 represents a hydro-
gen, fluorine, chlorine or bromine atom or a hydroxy, methyl, methoxy or
trifluoromethyl group; and R2 represents a hydrogen atom or a methyl,
ethyl or benzyl group, whenever prepared by the process of Claim 23 or by
an obvious chemical equivalent thereof.
25. A process according to Claim 1 in which R1 (or R5) represents a
5-methoxy, 5-trifluoromethyl, 5-hydroxy or 2-, 4-, 5- or 6-methyl group
or a hydrogen atom or a chlorine atom in the 2-position.
26. A compound as claimed in Claim 2 wherein R1 is as defined in
Claim 25 whenever prepared by the process according to Claim 25 or by an
obvious chemical equivalent thereof.

27. A process according to Claim 25 in which R2 is a hydrogen atom,
a benzyl group, an ethyl group or a methyl group, R2' or R6 is a hydrogen
atom, a benzyl group, an ethyl group, a methyl group or a benzyl group,
R8 is phenyl, and R4 is a methyl group or a hydrogen atom.
28. A process according to Claim 1 in which R1(or R5) is 5-hydroxy,
R2' is benzyl, R3 is methoxy, R4 is methyl or hydrogen and R6 is hydrogen.
29. A process according to Claim 1(b) in which 2-amino-3-(3,5-di-
hydroxyphenyl)-1-propanol hydrobromide is prepared by demethylating
2-amino-3-(3,5-dimethoxyphenyl)-1-propanol or an acid addition salt thereof
by reaction with hydrogen bromide.
30. A process according to Claim 29 in which the starting material
is prepared by reducing 3,5-dimethoxyphenylalanine methyl ester by reaction
with lithium aluminium hydride.
31. A process according to Claim 29 in which the starting material
is prepared by catalytically hydrogenating 1-(3,5-dimethoxyphenyl)-2-
nitroethane.
32. A process according to Claim 1(b) in which 2-amino-3-(3,5-
dihydroxyphenyl)-1-propanol hydrobromide is prepared by demethylating and
hydrolyzing 2-benzamido-3-(3,5-dimethoxyphenyl)-1-propanol.
33. A process according to Claim 32 in which the demethylation and
hydro b sis is effected by reaction with 6N hydrochloric acid.
34. A process according to Claim 32 in which the starting material
is prepared by reducing N-benzoyl-3-(3,5-dimethoxyphenyl)alanine methyl
46

ester by reaction with sodium borohydride.
35. A process according to Claim 1(a) in which 2-amino-3-(3,5-
dihydroxyphenyl)-1-propanol hydrochloride is prepared by reducing N-
benzoyl-3,5-dihydroxyphenylalanine methyl ester by reaction with sodium
borohydride and hydrolyzing the 2-benzamido compound so obtained by
reaction with hydrochloric acid.
36. 2-amino-3-(3,5-dihydroxyphenyl)-1-propanol hydrobromide whenever
prepared by the process of Claim 29 or 32 or by an obvious chemical
equivalent thereof.
37. 2-amino-3-(3,5-dihydroxyphenyl)-1-propanol hydrochloride when-
ever prepared by the process of Claim 35 or by an obvious chemical
equivalent thereof.
47

Description

1041S~6
The present invention relates to propanol derivatives and their
acid addition salts, as well as to processes for the production thereof.
The novel compounds possess interesting physiological properties.
According to one feature of the present invention there are
provided compounds of the formula:-
OH
~ CH2-fH-CH20H (I)
R NH-R
1' ,'.
(wherein R1 represents a hydrogen or halogen atom, a hydroxy or trifluoro-
methyl group or an alkyl or alkoxy group with 1 to 4 carbon atoms; and R2
represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or a
benzyl group) and pharmaceutically acceptable acid addition salts thereof.
The compounds of formula I as hereinbefore defined contain an
asymmetric carbon atom and thus ~ay exist not only in racemic form but
also in the form of optically active isomers ile~L the D and the L-isomers.
It ~ill he appreoi~ted that sll such fOr~J of the compo~ndY of lor ul-
'''~ ' '' '
: '
; " ~ '
~3~ ''`~ ' '
~ -2- ~ ~
.. ~, :. ...
. :. . . . . :

~041546
I (and acid addition salts thereof) are within the scope
of the present invention.
The acid addition salts useful for incorporation
in pharmaceutical compositions are physiologically
compatible acid addition salts. Other acid addition
salts may however be useful in the preparation of
compounds of formula I and physiologically compatible
acid addition salts thereof.
The compounds of general formula I according to
the invention and the physiologically compatible acid ~ ~ -
addition salts thereof possess interesting physiological -i ;
properties. In particular compounds according to the
invention in general possess sympathicomimetic properties
and are potentially useful as cardiac and circulation `;
agents. Moreover the compounds of formula I according
to the invention and the physiologically compatible acid
addition salts are potentially useful as agents for
increasing blood pressure, the effect of these compounds
. . ~ , , ~
being maintained for a relatively long period of time. -
Compounds of the present invention which have been tested
have been found capable of maintaining their physiological
activity for a longer period than commercial preparations
at present on the market and possessing a similar
- 3 -

1041546
physiological activity. In particular the half-life
time of activity of 2-amino-3-(3,5-dihydroxyphenyl)-1-
propanol (which is a compound of the present invention)
has been found to be about 3 times as long as the half-
life time of activity of 1-(3-hydroxyphenyl)-2-ethyl-
amino-ethanol. -`
Furthermore compounds according to the invention may
serve as intermediates in the preparation of other
physiologically active compounds.
Preferred compounds according to the present
invention, by virtue of their especially favourable
physiological activity include compounds of formula I ~-
as hereinbefore defined (wherein Rl represents a
hydrogen, fluorine, chlorine or bromine atom or a
lS hydroxy, methyl, methoxy or trifluoromethyl group and
R2 represents a hydrogen atom, or a methyl, ethyl or `
benzyl group and the acid addition salts thereof, `
Particularly preferred compounds of the present invention,
by virtue of their particularly favourable physiological
activity, include those preferred compounds, in which
Rl represents a chlorine atom, or a 5-hydroxy, methyl,
methoxy or trifluoromethyl group e.g. 2-amino-3-(3,5-
- 4 - ;
.

1041546
-dihydroxyphenyl)-1-propanol and the pharmaceutically acceptable acid
addition salts thereof. According to a further feature of this invention
there is provided a process for the preparation of a compound of the
formula:
OH
~ CH2-~CH-CH20H (I)
R1 2
'
'
wherein R1 represents a hydrogen or halogen atom~ a hydroxy or trifluoro-
methyl group or an alkyl or alkoxy group with 1 to 4 carbon atoms; and :
R2 represents a hydrogen atom~ an alkylggroup with 1 to 4 carbon atoms or
a benzyl group or a pharmaceutically acceptable acid addition salt thereof~ . :
which comprises either:~reducing a compound of the formula~
OH
~H-R ' (II)
",,- :. . ~ .:
wherein R1 is as defined above~ R21 represents the radical R2 or an acyl
group with 1 to 4 carbon atoms or a benizo~l group, and R3 represents an
optionally substituted alkoxy group and where R21 is an acyl group as - : -
hereinbefore defined, deacylating the product so obtained;~orsubjecting
a compound of the formula:-
~ CH2 _ IH _ CH20H (I )
R5 6
wherein R4 represents a hydrogen atom or a group removab~e by ether
splitting~ hydrolysis or by hydrogenolysis~ R5 represents the radical R1 ~ :
as defined above or the g~oup - OR7 in which R7 represents a group ~. -.
b: . . -.
~, _S_ ,''" ' '' .-

104154~;
removable by ether splitting, hydrolysis or hydrogenolysis, and R6
represents the radical R2 or a group removable by hydrogenolysis, with
the proviso that at least one of R4, R6 and R7 represent a removable
protecting group;(~or reducing a compound of the formula:- -
OH
~ CH2 _ ICH _ CH20H (IV)
Rl 2
wherein Rl is as defined above;~4-~ for the preparation of a compound of
formula I in which R2 represents an alkyl group with 1 to 4 carbon atoms
or a benzyl group, by alkylating or benzylating a compound of the formula:-
OH .
~ CH2-- ICH--CH20H (V)
Rl 2
wherein Rl is as defined above, either directly or by reaction with the ;~
appropriate aldehyde with 1 to 4 carbon atoms or benzaldehyde followed by
reductionS(~rfor the preparation of a compound of formula I in which R2
represents an alkyl group of 1 to 4 carbon atoms or a benzyl~group,
reducing a compound of the formula:-
OH
~ CH2 _ ICH _ CH20H (VII)
Rl ~ NH - COR
wherein Rl is as defined above and R8 represents a hydrogen atom~ an
alkyl group with 1 to 3 carbon atoms or a phenyl group, and wherein any
of steps (a) to (e) may be followed by the additional step of converting
a base of formula I obtained into a corresponding pharmaceutically
acceptable acid addition salt.
~ -Sa-
~'
.

10415~6
Thus, the compounds of formula I (as hereinbefore definedl are,
for example, prepared by one of the following processes (a) to (e), which
processes constitute further features of the present invention a) reducing
a compound of the formula:
OI H
~ CH2-CH-CQR3 (II)
Rl NH-R2~
(wherein Rl is as hereinbefore defined~ R2~ represen~s the radical R2 or
an acyl group with 1 to 4 carbon atoms or a benzoyl group, and R3
represents an optionall~ substituted alkoxy group) with a complex hydride
and, where a compound is obtained~ wherein R21 represents an acyl group
deacylating said compound whereby a compound of formula I is obtained.
The reduction is preferably effected by the use of a strongly effective
hydride e.g. lithium aluminium hydride or sodium di(methoxyethoxy)aluminium-
hydride (SDMA). The reduction may also be effected by the use of a weaker
reducing complex hydride, e.g. lithium borohydride, c~lGium borohydride or
sodium borohydride.
.. .
,', ' '' ~''''
', , ~
.',' ' ' ' .' .
~, .
-5b- -
, , ' ,
~, .,-

~041546
Where, however, a compound of formula II is used as starting material inwhich R2' represents an acyl group and a weaker reducing complex hydride
is employed the amide grouping in the c0mpound of formula II undergoes
virtually no reaction. In this case the acyl grouping is removed sub-
sequently by conventional methods e.g. by treatment with hydrochloric
acid to form a compound of formula I as hereinbefore defined (in which R2
represents a hydrogen atom). Where, however, a compound of formula II is
used in which R2' represents an acyl group and a strongly effective com-
plex hydride is employed the acyl grouping is reduced to the corresponding
10 hydrocarbon group i.e. a compound of formula I is obtained in which R2
represents an alkyl group with 1-4 ~arbon atoms or a benzyl group.
b) subjecting a compound of formula:-
OR
L~ '. . .
CH2-CH-CH20H (III) ;
NH-R
R 6
~ '
q~ '
: . . ~
~' , ' , : -~
, ' , - ' ; -
-

1041S46
wherein R4 represents a hydrogen atom or a group removHble by ethersplitting, hydrolysis or hydrogenolysis~ R5 represents the radical R1 as
hereinbefore defin~d or the group -OR7 (in which R7 represents a group
removable by ether splitting, hydrolysis or hydrogenolysis and R6
represents the radical R2 or a group removable by hydrogenolysis , with
the proviso that at least one of R4, R6 and R7 represen~ a removable
protecting group as defined above, to ether splitting,~hydrolysis or
hydrogenolysis~ whereby the said compound of formula III is converted into
a compound of formula I.
10The -OH protecting groups may, for example, be groups removable
by hydrolysis, hydrogenation, ether cleavage or deacylation. Hydroxyl
protecting groups which may be removed by ether cleavage or deacylation
include, for example, alkyl groups such as methyl or benzyl groups or acyl
. . . .
groups. Removal of the -OH protecting grDups may be effected in a manner
known per se. Thus hydrogenation may~ for example~ be effected by the use `
o~ hydrogen and conventional hydrogenation catalysts~ e.g. platinum,
palladium or Raney-nickel and ether cleavage and deacylation may, for
example, be cffected by the use of hydrobromic acid, hydrochloric
!~- - .
S, ~ ~ ,
'`' .
~.,,,, . ~ ,,,
~ - . . .
. ' ' .
.,; , ' .
,~ ' . . ...
~7~
rr~
,, , ~ , ~ ", ,~ , ,, ",, ,",, ," ~ ,"

~04154f~
acid, boron trifluoride etherate, boron tribromide or aluminium chloride.
c) reducing a compound of the formula:-
OH
CH2-CH-CH20H (IV)
Rl N02
(wherein Rl is as hereinbefore defined) whereby a compound of formula I is
obtained.
The reduction may, for example, be effected catalytically with
hydrogen and a conventional hydrogenation catalyst, e.g. platinum,
palladium or Raney nickel. d) for the preparation of compounds of formula I
as hereinbefore defined (wherein R2 represents an alkyl group with 1-4 ~
carbon atoms or a benzyl group), the Al~ylation of a compound of the for- ~ -
mula--
~H
,~ CH2-CH-CH20H (V)
R1 2
either directly or by reaction with the appropriate aldehyde with 1-4
carbon atoms or benzaldehyde followed by reduction,
~.,,. i , . ~ .
- . "
~ ', ,,
..

1041546
(wherein Rl is as hereinbefore defined) whereby a
compound of formula I (wherein R2 represents an
alkyl group with 1 to 4 carbon atoms or a benzyl
group) is obtained.
e) for the prFparation of compounds of formula I
as hereinbefore defined (wherein R2 represents an ~ -
alkyl group with 1-4 carbon atoms or a benzyl group),
the reduction of a compound of the formula:-
OH
~ CH2-CH-CH20H (VII)
Rl NH-COR8
(wherein Rl is as hereinbefore defined and R8
represents a hydrogen atom, an alkyl group with 1-3 ~ -
carbon atoms or a phenyl group) whereby a compound of -
formula I (wherein R2 represents an alkyl group with 1-4
carbon atoms or a benzyl group) is obtained.
The reduction is preferably effected by the use
of a complex hydride e.g. lithium aluminium hydride
or S.D.M.A. --
The compounds of formula VII are preferably first ~
'.''. ' ' ''
_ g
,. . .
~ . .
- . ~- ,, . . . . :
:; . - . ~" - . : . .,
., .
.. . . . . , , - -
. , ,.-, .~ ` ' .,,. ~ ''' ' ; ~'.
... . ,.. . ,, . :

1041546
prepared by acylating a compound of the formula:-
OH
~ CH2-CH-CH2OH
Rl NH2 (V)
(wherein Rl is as hereinbefore defined) whereby a
compound of formula VII (as hereinbefore defined) is
obtained.
If desired, the bases of formula I may be
converted according to conventional methods into
their acid addition salts e.g. their physiologically
compatible acid addition salts, or where the compounds -
are obtained in the form of salts, these salts may,
if desired, be converted into salts with other acids
or into the corresponding free bases.
Compounds of general formula I as hereinbefore
defined may occur in the form of racemates. Any
racemates present may, if desired, be resolved into
their optically active isomers by conventional methods e.g,
by means of optically active acids. Thus, for example,
the optically active isomers may be prepared either by
starting from optically active starting compounds in the
- 10 -
,~ ~

~041546
processes of the present invention or by resolving the
racemates obtained as reaction products into their
,: '- . . . .
optical isomers in conventional manner.
The starting materials for the processes of the
present invention may be prepared by processes known
per se. The a-amino acid esters required for processes
(a) and (b) may be obtained, for example, via the
corresponding azalactones or by reaction of the
correspondingly substituted benzyl halide wLth
acetamido-cyano-acetates or -malonic esters.
", :-' .'
The starting materials for process (c) may, ~ ;
for example, be obtained by reacting a correspondingly
substituted l-phenyl-2-nitroethane with paraformaldehyde. - -
According to a still further feature of the present
i . ,,
invention there are provided pharmaceutical compositions ` -
comprising as active ingredient at least one compound -
of formula I as hereinbefore defined or a physiologically
compatible acid addition salt thereof in association with
a pharmaceutlcal carrier or excipient. The compositions '
may be presented in a form suitable for oral, rectal or
parenteral administration. Thus, for example, compositions
_11- ~'"
.: '
.,
, . . . .. , ~.
, ' ~ . ,' ' ' - ' ' ,'` ' ,
. .

104~546
for oral administration may be solid or liquid and may
take the form of granules, tablets, coated tablets,
capsules, tinctures, syrups, pills, emulsions, suspensions,
powders, or drops, such compositions comprising carriers
or excipients conventionally used in the pharmaceutical
art. Thus, for example, suitable tabletting excipients
include lactose, potato and soluble starches and
magnesium stearate.
For parenteral administration, the carrier may be
a sterile, parenterally acceptable liquid such as
sterile water, or a parenterally acceptable oil e.g.
arachis oil, contained in ampoules. Compositions for
rectal administration may take the form of suppositories,
the carrier comprising a suppository base.
Advantageously, the compositions may be formulated
as dosage units, each unit being adapted to supply a
fixed dose of active ingredient. Tablets, coated
tablets, capsules, suppositories and ampoules are
examples of suitable dosage unit forms. Each dosage
unit preferably contains 1 to 100 mg and especially
5 to 20 mg, of active ingredient. -
- 12 - ~
:
:',, '

1041546
The following examples illustrate the preparation
of compounds according to the invention, and also :
phanmaceutical compositions containing such compounds ~.
as active ingredients~
,
- 13 - .
:.
.
: . .
.- . - - . ,. , . , .. .. :
.:, ,: , .. , .. ~,: . . . . .
~ . - . . . :
. : - : . . . ,, .
- . . . .

10~1546
Example 1
2-Amino-3-(3,5-dihydroxvphen~l)-1-propanol-hydrobromide
a) 2-Amino-3-(3,5-dimethoxyphenyl)-l-propanol-hydr
_______________________ ___ _____ __ ______ ___
chloride
________
6 8 g (28 mmol) of 3,5-dimethoxyphenylalanine-
methyl ester are dissolved in 35 ml of absolute
tetrahydrofuran and, at 20 to 30C, added dropwise to a
stirred suspension of 3.2 g (89 mmol) of lithium aluminium
hydride in 35 ml of absolute tetrahydrofuran. The
mixture is refluxed for 2 hours, cooled and decomposed
cautiously with water. Subsequently, the mixture thus
obtained is extracted with ethyl acetate, the organic `
phase is dried over sodium sulfate and the solvent distilled ~-
off in vacuo. The residue is converted into the
hydrochloride with ethereal hydrochloric acid. ~
Yield: 6.5 g (65% of theory); ~ ;
M.p. 165C.
b) 2-Amino-3-(3,5-dihydroxyphenyl)-l-pro~anol-hydr
__________________ ------------ ,
bromide
_______ .: . .
4.5 g (18.5 mmol) of 2-amino-3-(3,5-dimethoxyphenyl)-
l-propanol hydrochloride are refluxed together with 45 ml
of hydrobromide for one hour. The excess hydrobromic ~ ~-
- 14 -
:

1041546
acid is then distilled off in vacuo and the residue
is dehydrated azeotropically. The crystalline residue
is recrystallized from isopropanol/ether.
Yield: 1.8 g (37% of theory);
M.p. 118-120C.
Example 2
2-Benzylamino-3-(3-hvdroxy-4-methylphenvl)-1-propanol-
hydrobromide
a) 2-Benzylamino-3-(3-methoxy-4-methylphenyl)
______ __________________ _______ _ ___ _____
proPanol hydrochloride
55.5 g (0.16 mol) of N-benzcy1-3-(3-methoxy-4-
methylphenyl)-alanine-ethyl ester (m.p. 133C) are dissolved
in 550 ml of absolute tetrahydrofuran and slowly added
dropwise to a stirred suspension of 37 g (0.98 mol) of
lithium aluminium hydride in 1850 ml of absolute tetra-
hydrofuran under a nitrogen atmosphere. When the addition
has been completed, the mixture is refluxed for 5 hours,
allowed to stand overnight and decomposed slowly with
water. The inorganic precipitate is filtered off with
suction and washed with tetrahydrofuran. The solvent is
distilled off in vacuo, the residue is taken up in ether
and treated with water. The ether phase is dried over
- 15 -
: , . - ~.

~04~S46
sodium sulfate and distilled off. The residue is
recrystallized from petroleum ether. Yield: 45.0 g (97.5%
of theory). The base is dissolved in ethyl acetate and
,~
on the addition of ethereal hydrochloric acid converted
S into the hydrochloride.
Yield: 49.5 g (95% of theory); m.p. 191C.
b) 2-Benzylamino-3-(3-hydroxy-4-methyl~?henyl)~
______ _____________ ____ _______ _ ___ ____ .
propanol
__ ____ :
20 g (62 mmol) of 2-benzylamino-3-(3-methoxy-4-
methylphenyl)-l-propanol hydrochloride in 200 ml of 48%
hydrobromic acid are refluxed for 1 hour. The mixture --
is cooled, the precipitated crystals are filtered off .~ -
with suction and recrystallized from water. Yield: 21.5 g
(98.5% of theory), m.p. 199C.
Example 3
,,~'.` ~ ".. ~ .
2-Amino-3-(3-hydroxy-4-methylphenvl)-1-propanol-hydrobromide
21.5 g (61 mmol) of 2-benzylamino-3-(3-hydroxy-4-
methylphenyl)-l-propanol hydrobromide (see Example 2) are
dissolved in 250 ml of methanol and after the addition of ~-
6 g of palladium/charcoal (5%) debenzylated catalytically
at 60C and 5 atmospheres. When the hydrogenation is
- 16 -
'~
- :
', '
- .. - .. :... , ~ . . . . ... . . ..

104~S46
completed, the mixture is filtered off, the methanol is
distilled off in vacuo and the residue is dissolved hot
_ ~ .
in acetonitrile. On cooling, the title compound crystallizes
out and is filtered off with suction and dried.
Yield: 13 g (81.5Z of theory).
M.p. 115-117C.
Example 4
2-Amino-3-(3-hydroxv-5-methvlphenyl)-1-Propanol hvdrobromide ~-
a~ 3-(3-Methoxy-5-methylphenyl)-alanine-ethyl ester -
___________ _______ _ ___ _____________ _______
56 g (0.33 mol) of 3-methoxy-5-methyl-benzylchloride
are added dropwise to a solution of 56 g (0.33 mol) of
acetamidocyanoethyl acetate and 7.8 g of sodium in 330 ml
of ethanol. The mixture is refluxed for 4 hours, filtered
off with suction to remove the precipitated sodium chloride
and the alcohol is then distilled off in vacuo. The
residue is saponified by boiling with 117 g of potassium
~ . .
hydroxide in 920 ml of water for 20 hours. The resulting
product is acidified with concentrated hydrochloric acid
and evaporated to dryness.
The amino acid is extracted by treating the amino
acid containing mixture twice each time with 1 ltr. of
- 17 -

104~46
ethanol. The alcohol is distilled off and the hydrochloride
of the amino acid obtained as residue is recrystallized
from acetonitrile.
Yield: 46 g (57% of theory), m.p. 248C.
The ethyl acetate is obtained in 65% yield by azeotropic
esterification. The hydrochloride melts at 184-185C. -
b) 2-Amino-3-(3-methoxy-5-methylphen~l )-l-propanol
_________-------- : ,
hydrochloride
___________
33 g of 2-amino-3-(3-methoxy-5-methylphenyl)-alanine
ester hydrochloride are suspended in ether and converted
into the base on the addition of dilute ammonia. The -
.. . .
base is dried over sodium sulfate and the ether is distilled
off in vacuo. The resulting product is then diss~olved again -
in 330 ml of absolute ether and added dropwise to the
stirred suspension of 13.7 g of lithium aluminium hydride
in 700 ml of absolute ether. The resulting product is re- -~
fluxed for 5 hours, decomposed with water, filtered off
with suction and evaporated in vacuo. The residue is
dissolved in acetonitrile and mixed with the calculated
quarltity of ethereal hydrochloric acid. The precipitated - -
hydrochloride is filtered off with suction and dried. : -
- 18
... . ..
,, ; . -. ~
- . - . . . , - . . .
., ~ . , - . .- : .. . .
- . .
.. .. ..

1041546
Yield: 23 g (83% of theory), m.p. 204 - 205C.
c) 2-Amino-3-(3-hydro ~-5-methylphenyl2-l-propanol .-,-
hydrobromide
____________ .
23 g (0.1 mol) of 2-amino-3-(3-methoxy-5-methyl-
phenyl)-l-propanol hydrochloride are refluxed for one
hour after the addition of 230 ml of 48% hydrobromic
acid. A part of the hydrobromic acid is distilled off,
cooled and filtered off with suction. The product thus
obtained is recrystallized from aqueous acetonitrile.
Yield: 20 g (76% of theory), m.p. 160C.
Example 5
2-Amino-3-(3-hydroxy-4-methoxyphenyl)-1-propanol ~ --
ydrochloride
6 g (18.6 mmol) of 2-benzylamino-3-(3-hydroxy-4-
methoxyphenyl)-l-propanol hydrochloride are dissolved in
60 ml of methanol. After the addition of palladium/char-
coal (5%) the mixture is debenzylated catalytically. After
uptake of the calculated quantity of hydrogen, the
catalyst is filtered off, the solvent is distilled off
in vacuo and the residue recrystallized from acetonitrile.
Yield: 4g (92% of theory), m.p. 181-182C.
- 19 -
; :
' , '' ' - ~ '.',
.- .

1041546
Example 6
2-Amino-3-(3-hydroxyphenyl)-1-propanol-hydrobromide ~ -
a) 2-Amino-3-(3-methoxyehenyl2-1 proeanol hydrochloride
29 g (0.139 mol~ of 3-(3-methoxyphenyl)-alaninemethyl
ester are dissolved in 170 ml of absolute tetrahydrofuran
and added dropwise to a stirred suspension of 10.6 g
(0.278 mol~ of lithium aluminium hydride in 170 ml of
absolute tetrahydrofuran. After 2-hours' boiling, ~
the reaction mixture is further processed as described ~ v
in the preceding Examples. The hydrochloride of 2-amino-
3-(3-methoxyphenyl)-1-propanol is obtained in a yie~t
of 26.5% of theory with a melting point of 145~. -
b) 2-Amino-3 (3 hydroxyehenyl2 1 propanol hydrobromide
8 g of 2-amino-3-(3-methoxyphenyl)-1-propanol
hydrochloride are refluxed in 80 ml of 48% hydrobromic
acid for 1 hour. Subsequently, the reaction mixture is
evaporated to dryness in vacuo, the water is removed by ~-
distillation after the addition of xylene and the residue
is recrystallized from glacial acetic acid.
Yield: 6 g (66% of theory), m.p. 150-152C.
- 20- -
.,
'~
. .
- : . . .. , ~ , . . . .

1041546
Example 7
2-Amino-3-(3,5-dihydroxyphenyl)-1-propanol-hydrobromide
a) l-(3,5-Dimethoxy~henyl)-2-nitroethane
_______________ ___ ________________
27 g (0.129 mol) of 3,5-dimethoxy-~-nitro-styrol
are dissolved in 540 ml of benzene. Nitrogen is passed
through the solution in the presence of 1.3 g of tris-
(triphenylphosphine)-rhodium-I-chloride as catalyst. Then,
at 60C and 5 atmospheres pressure the calculated quantity
of hydrogen is introduced. When the hydrogenation is
completed, the benzene is distilled off and the residue
triturated with ether. This processing causes the catalyst
to precipitate. The catalyst is filtered off with suction,
the ether is distilled off and the product remaining is
recrystallized from methanol.
Yield: 21.3 g (78.S% of theory), m.p. 51-53C.
b) 3-~3~5-Dimethoxyehenyl)-2-nitro-1-eroeanol
__ _ __________ ___ _____________ __ _____
10 g (47.4 mmol) of 1-(3,5-dimethoxyphenyl)-2-nitro-
ethane are dissolved in 100 ml of ethanol. 1 ml of conc.
sodium hydroxide solution is then added to the solution.
5 g (50 mmol) of a 30% formalin solution is then added
dropwise slowly, the temperature being kept below 20C.
- 21 -
- :: . . . .
,

104~546
The reaction mixture is allowed to stand for 70 hours at
room temperature; it should be observed that the solution
maintains an alkaline reaction during this time. The
solution is acidified with 2 N acetic acid and the solvent
is distilled off in vacuo. The resultant product is
distributed between ethyl acetate/water, the organic
phase is dried over sodium sulfate and the solvent is
distilled off in vacuo. The residue is triturated with
warm toluene, whereby crystallization takes place. -~
Yield: 8.9 g (78% of theory), m.p. 81-83C.
c) 2-Amino-3-(3,5-dimethoxyphenyl2-l-~ro~anol hydro-
chloride
________ ~ ~ . .
8.5 g of 3-(3,5-dimethoxyphenyl)-2-nitro-1-propanol
are dissolved in 100 ml of methanol and after addition
of platinum dioxide it is hydrogenated under nonmal
conditions. After uptake of the calculated quantity of -
.. . .. .
hydrogen, the catalyst is filtered off a~d the solution
evaporated to dryness in vacuo. The residue is dissolved
in acetonitrile; on the addition of the calculated quantity
of ethereal hydrochloric acid the hydrochloride of melting
point 165C is obtained.
- 22 -
- ~ . ... - :, - . : -.. . ..
.- .
. . .
.

1041546
Yield: 5.3 g (71% of theory).
In order to produce 2-amino-3-(3,5-dihydroxyphenyl)-
l-propanol-hydrobromide, the resultant product is further
processed as described in Example 1.
Example 8
2-Amino-3-(3-hydroxy-5-trifluoromethyl-phenyl)-1-propsnol-
hydrobromide
a) 3-Methoxy-5-trifluoromethyl-benzaldehyde
________ ________________ ___________ __
125 g of 3-methoxy-5-trifluoromethyl-aniline are
diazotized and reacted according to the method of BEECH
(J. Chem.Soc. 1 _ , 1297) to give 3-methoxy-5-trifluoro-
methyl-benzaldehyde. (B~p~o 1 58 - 60C, n20 = 1.4833).
b) N-Benzoyl-3-methoxy-5-trifluoro-methylphenyl-alanine- --
_______ __________ _________________ _ ___ _________
methylester
____ ______ .
3-methoxy-5-trifluoromethylbenzaldehyde is reacted
with hippuric acid to give the azalactone (m.p. 149 - 150C).
By means of boiling in methanol in the presence of catalytic
quantities of potassium carbonate the a-benzamido-3-
methoxy-5-trifluoromethyl-methyl-cinnamate is obtained
(m.p. 143C), which is hydrogenated catalytically to give
the N-benzoyl-3-methoxy-5-trifluoromethylphenyl-alanine-
methyl ester (m.p. 133C).
- 23 -
..
:. . ..... : .-, . ..
"- :. ., ' ~. ,, .: ,' ' ';;`

104~546
c) 2 Benzylamino-3-(3-methoxy-5-trifluoromethylphen
l-propanol hydrochloride
__ __ ______ ___________ ~
17 g of the ester mentioned under (b) are reduced -
to the amino alcohol according to the method described
~-
in Example 2(a). The melting point of the hydrochloride
amounts to 161C. - -
d) 2-Benzylamino-3-(3-hydroxy-5-trifluoromethylphenyl)-
______ _____________ ____ ________________ _ ___ ___ .
l_eropanol hydrobromide
15 g of 2-benzylamino-3-(3-methoxy-5-trifluoro-
10 methylphenyl)-l-propanol hydrochloride are demethylated
by boiling with 48% hydrobromic acid for one hour. Then,
the reaction mixture is cooled, the precipitated crystals -
are filtered off with suction and dried. -
Yield 11 g; m.p. 206 - 207C.
15 e) 2-Amino-3-(3-hydroxy-5-trifluoromethylphenyl)-1-
__________ ___ ____ ___________--___ -- -------------- .~ .
propanol hydrobromide
Debenzylation is effected catalytically in methanol.
After uptake of the calculated quantity of hydrogen, the
catalyst is filtered off, the solvent is distilled off -
in vacuo and the residue recrystallized in acetonitrile. ;
The 2-amino-3-(3-h~droxy-5-trifluoromethylphenyl)-1-propanol
hydrobromide melts at 155-156C.
- 24 - ;
.'~
,` '

1041546
Example 9
2-Amino-3-(2-chloro-5-hydroxyphenyl)-1-propanol hydrobromide
The azalactone is obtained in the manner described in
Example 8 starting from 2-chloro-5-methoxy-benzaldehyde
by condensation with hippuric acid (m.p. 167C), from
which the corresponding hydroxymethyl-cinnamate (m.p.
121-123C) is obtained following which reduction with
lithium aluminium hydride yields the hydrochloride of
2-benzylamino-3-(2-chloro-5-methoxyphenyl)-1-propanol
(m.p. 167 - 168C). After catalytic debenzylation
(m.p. 153 - 155C) and demethylation with 48% hydrobromic
acid, the hydrobromide of 2-amino-3-(2-chloro-5-hydroxy-
phenyl)-l-propanol of m.p. 174-175C is obtained.
Example 10
,2-Ethvlamino-3-(3,5-dihydroxyphenvl)-1-propanol hvdro-
bromide
a) N-Acetyl-3 5-dimethoxyphenyl-alanine-methylester
______ ___~__________ ___ ______________ ______
3,5-dimethoxy-benzaldehyde is condensed with aceturic
acid, yielding 45% of a product having a m.p. 142-
143C. By refluxing in methanol in the presence
of potassium carbonate and subsequent hydrogenation
- 25 -
.. . . :- . ... , . - . . ~; . ., . ............ . , , :
. , .~ ~ . .. . ......

10415~S
the N-acetyl-3,5-dimethoxyphenyl-alanine-methyl
ester (m.p. 110 - 111C) is obtained. -~
b) 2~Ethylamino-3-(3~5-dimethoxyehenyl)-i-propan
__ ___________ __________ ___ _____ __ ____ ~ .
hydrobromide
__________
42 g of N-acetyl-3,5-dimethoxyphenylalaninemethyl
ester are reduced in absolute tetrahydrofuran with
lithium aluminium hydride to yield the 2-ethylamino-
3-(3,5-dimethoxyphenyl)-1-propanol (m.p. 82 - 83C).
The hydrobromide melts at 175C.
10 c)2-Ethylamino-3-(3,~5-dihydroxy~henyl)-1-~ropanol .,'. -
_____ ___________ _____ --_-------------------- .. ~ , :.
hydrobromide -
__________ .. .
10 g of 2-ethylamino-3-(3,5-dimethoxyphenyl)-1-
propanol hydrobromide are demethylated by boiling
with 48% hydrobromic acid. After distilling off
the excess hydrobromic acid, the remaining residue
is recrystallized from acetonitrile. The 2-ethyl-
amino-3-(3,5-dihydroxyphenyl)-1-propanol hydro-
bromide melts at 167 - 168c.
Example 11
20 2-Methylamino-3-(3,5-dihydroxvphenyl-1-propanol hYdro
.
bromide
The hydrobromide of 2- `~-
methylamino-3-(3,5-dimethoxyphenyl)-1-propanol, m.p.
- 26 -
-

~041546
142C, is obtained by a process similar to that of
Example 10 starting from N-formyl-3,5-dimethoxyphenyl-
alanine-methyl ester by reduction with lithium aluminium
hydride. The demethylation with 48% hydrobromic acid
yields 2-methylamino-3-(2,5-dihydroxyphenyl)-1-propanol
hydrobromide, m.p. 183 - 186C.
Example 12
2-Amino-3-(3-hydroxv-2-methvlphenyl)-1-propanol hydrobromide
a) N-Benzoyl-3-methoxy-2-methylPhenylalanine-methylester
3-methoxy-2-methyl-aniline is reacted according
to BEECH (see Example 8) to yield 3-methoxy-2-methyl-
benzaldehyde. Reaction of this latter compound with
hippuric acid yields the corresponding azalactone (m.p.
166C), which is then reacted by boiling with methanol/
potassium carbonate followed by catalytic hydrogenation
to yield the N-benzoyl-3-methoxy-2-methylphenyl-alanine
methyl ester (m.p. 143-144C.).
b) 2-Amino-3-(3-hydroxy-2-methylphenyl)-l-eropan
______ _------------ :
hydrobromide
N-benzoyl-3-methoxy-2-methylphenyl-alanine-methyl
ester reacts with lithium aluminium hydride to yield
- 27 -
:; .
.- .
... '~: . -
'.

1~4:1546
2-benzylamino-3-(3-methoxy-2-methylphenyl)-1-propanol.
The hydrochloride melts at 174C. By means of boiling
with 48~/o hydrobromic scid, the 2-benzylamino-3-(3~
hydroxy-2-methylphenyl)-1-propanol-hydrobromide (m.p. -
~ 153C) is obtained. This latter compound is debenzylated
catalytically to yield the 2-amino-3-(3-hydroxy-2-
methylphenyl)-l-propanol hydrobromide. ;
. .
(m.p. 166C).
Example 13
2-Amino-3-(3-hydroxy-6-methylphenyl)-1-propanol hydro-
bromide ~;
a) N-Benzoyl-3-methoxy-6-methylehenyl-alanine-methyl-
ester
_____ ,,
2,5-cresotic acid is methylated with dimethylsulfate
to yield 5-methoxy-o-toluylic acid (m.p. 152-154C).
According to the Rosenmund method, 5-methoxy-o-tolualde-
hyde (b.p.o 3 75C) is obtained via the acid chloride
(b.p.0 '3 81-83C). As described in Example 12, the :` `
, ~.
azalactone (m.p. 170-171C) as well as the N-benzoyl-3-
methoxy-6-methylphenyl-alanine-methyl ester (m.p. 98C)
are produced.
- 28 -
..
, ,
,; . : - . . ,, , ., . :
~, . . . . . . .
. . .
,, - . , , . - , ~ , .
.

1041546
b) 2-Amino-3-(3-hydroxy-6-methylphenyl)-l-ero~anol
______________ ____ _______ _ ___ _____ __ ____
hydrobromide
_ _ _ _ _ _ _ _ _ _
The 2-benzylamino-3-(3-methoxy-6-methylphenyl)-1-
propanol hydrochloride obtained by reduction with lithium
aluminium hydride is first demethylated (m.p. 166-167C)
and then catalytically debenzylated to yield 2-amino-3-
(3-hydroxy-6-methylphenyl)-1-propanol hydrobromide
(m.p. 143C).
Example 14
2-Amino-3-(3,5-dihvdroxvphenyl)-1-propanol hvdrochloride
a) 2-Benzamido-3-(3 5-dimethoxyphenyl)-l-propan
________________~__________ ___ _____ __ ____
To 34.3 g of N-benzoyl-3-(3,5-dimethoxyphenyl)-a~nine
methylester in 350 ml of tetrahydrofuran are added 4.2 g
of sodium borohydride, while stirring at room temperature.
The mixture is first stirred for 30 minutes and it is then
refluxed for 5 hours. After cooling, the solvent is ~.
distilled off in vacuo, the residue is suspended in -
.
water and acidified with acetic acid. The precipitating - ~
crystals are filtered off with suction, washed with ~ ;
water and dried. By recrystallization from toluene
e~zam;O~O
2-bonzamide-3-(3,5-dimethoxyphenyl)-1-propanol of
- 2g - ~, "
~ '
. '
- -$: . : , .. , - :
, i. : : ' .: . ~

104~546
m.p. 117-118C is obtained.
b) 2-Amino-3-(3~5-dihydroxy~henyl2-l-eropan
hydrochloride
_ _ _ _ _ _ _ _
21 g of 2-benzamido-3-(3,5-dimethoxyphenyl)-1-
propanol are refluxed in 200 ml of 6 N hydrochloric acid ~ -
for 8 hours. After cooling, the mixture is extracted
three times with chloroform and evaporated to dryness
in vacuo. The residue is recrystallized from glacial
acetic acid. The hydrochloride of the 2-amino-3-(3,5-
dihydroxyphenyl)-l-propanol melts at 167C.
Example 15
2-Benzylamino-3-(3-hydroxy-4-methoxyphenyl)-1-propanol
, :
hydrochloride
13 g of N-benzoyl-3-(3-hydroxy-4-methoxyphenyl)-
alaninemethyl ester (m.p. 11 -116C) are dissolved in
130 ml of absolute tetrahydrofuran and added dropwise
to a stirred suspension of 9 g lithium aluminium hydride
in 450 ml of absolute tetrahydrofuran. The mixture is -
refluxed for 6 hours, allowed to stand overnight and
decomposed with water. The precipitate is filtered off
with suction, extracted twice with dimethylformamide at
60C
- 30 -
- ~ ~
- . ,
. .
- . . .
.

10~546
and the two organic solutions are evaporated to dryness.
The residue is dissolved in 2 N hydrochloric acid, extr-
acted with ethyl acetate and made alkaline again by the
addition of potash. After drying over sodium sulfate,
the solvent is distilled off in vacuo. The residue
is dissolved in acetonitrile, mixed with the calculated
quantity of ethereal hydrochloric acid and filtered
off with suction.
Yield: 6 g (47% of theory), m.p. 128C.
ExamPle 16
2-Amino-3-(3,5-dihvdroxvphenyl)-1-propanol hvdrochloride
a) N-Benzoyl-3,5-dihydroxy-~henylalanine-methylester -~
31 g (0.067 mol) of 2-phenyl-4-(3,5-bisbenzyloxy-
benzylidene)-5-oxazolone are suspended in ten times the
quantity of methanol and, after the addition of 1 g of
anhydrous potash, refluxed for 10 minutes. The solution
obtained is filtered warm into a hydrogenation vessel ;
and hydrogenated after the addition of Raney-nickel until
the uptake of hydrogen is completed. The catalyst is
filtered off with suction and the methanol is distilled .
off in vacuo. The residue is dissolved in a little
... .
methanol
_ 31 -
. .
- ~. .~. . -. . ~ , - .. .

1041546
and brought to crystallization by the addition of water.
The precipitate is filtered off with suction and dried.
Yield: 18 g (85% of theory) f m.p. 168C.
b) 2-Benzamido-3-(3~5-dihydroxy~henyl)-1-~ro~anol
________________ _____ ____ ___ _____ __ ____
12.7 g (0.144 mol) of calcium chloride are
dissolved at room temperature in 360 ml of ethanol.
18 g of (0.057 mol) of N-benzoyl-3,5-dihydroxyphenyl-
alanine-methyl ester are then added and the mixture
is cooled to -10C. At this temperature 11 g (0.288 mol) ~ -
of sodium borohydride are cautiously added. When the ~
addition is completed, the reaction mixture is stirred ~ -
for 1 hour at -10C, 1 hour at -5C and two hours more
at 0C. The alcohol is distilled off in vacuo (temp-
erature of bath 40 to 50C). The residue is mixed with
lS water and, while cooling, acidified with 2 N hydrochloric ~-
acid. The product thus obtained is extracted 4 to 5 times
with hot ethyl acetate, dried over sodium sulfate and the
solvent is distilled off in vacuo. The residue is i -
dissolved in a little methanol and by adding water slowly
precipitated in crystalline form. The precipitate is
filtered off with suction and recrystallized several
- 32 - ;~
. . .
~ .~¢;.....
,

. ~04~546
times from ethyl acetate.
Yield: 12.5 g (76% of theory), m.p. 132-134C.
c) 2-Amino-3-(3,5-dihydroxyphenyl)-l-propan
__________________ ____ -------------- :
hydrochloride
___________ .
S 39 g (0.136 mol) of 2-benzamido-3-(3,5-dihydroxy-
phenyl)-l-propanol in 390 ml of 2 N hydrochloric acid
are refluxed for 18 hours. The reaction mixture is
cooled, the benzoic acid is extracted with chloroform
and the remainder is distilled to dryness in vacuo.
The residue is triturated with acetonitrile until
crystallization is achieved and the crystals are then
filtered off with suction. The hydrochloride of the
2-amino-3-(3,5-dihydroxyphenyl)-1-propanol is recry-
stallized from lS0 ml of glacial acetic acid in the
presence of 5 drops of 40% sodium bisulfite solution
and activated charcoal. .
Yield: 25 g (84% of theory), m.p. 166-167C.
Example 17 -
. . .
2-Benzvlamino-3-(3,5-dihvdroxyphenyl)-1-propanol
hydrobromide
15.7 g (0.05 mol) of N-benzoyl-3-(3,5-dihydroxyphenyl)-
- 33 -
.
,
.. ... ...... .
:. . ~ , ... ', . :. . . ' ~.

1041546
-alanine-methyl ester (m.p. 168C) are dissolved in
200 ml of absolute tetrahydrofuran and slowly added
dropwise to a stirred suspension'of 15.2 g (0.4 mol)
of lithium aluminium hydride in 600 ml of absolute -S tetrahydrofuran. The reaction mixture is refluxed
for 3 hours and allowed to stand overnight. The
excess lithium aluminium hydride is decomposed, filtered
off with suction and the residue extracted with warm
dimethylformamide. The organic phase is evaporated
in vacuo. The residue is dissolved in dilute hydrobromic
acid, filtered over activated charcoal and then
evaporated to dryness in vacuo. The hydrobromide of
2-benzylamino-3-(3,5-dihydroxyphenyl)-1-propanol
(m.p. 117-119C) thus obtained is recrystallized from
acetonitrile.
Example 18 ~ '
~- - .
2-Amino-3-(3-hYdroxy-6-methYlPhenyl)-l-propanol
hydrochloride -~
6 ~ ~n~/ -
10 g of 3-(3-hydroxy-S-methy~)-2-nitro-1-propanol,
prepared in a manner similar to Example 7, are dissolved
in 200 ml of methanol and after the addition of platinum
; :
- 34 -
.
,; , , , ,, , .:, :
.
. .
~ ' ~ . , ;" ~ - .

1041S46 :
oxide hydrogenated under normal conditions at room
temperature. After uptake of the calculated quantity
of hydrogen, the catalyst is filtered off and evaporated
to dryness in vacuo. The residue is dissolved in
.
dilute hydrobromic acid and the solution is evaporated ,~
to dryness in vacuo. The residue thus obtained is first -
triturated with acetonitrile and then recrystallized
from glacial acetic acid. The 2-amino-(3-hydroxy-6-
methylphenyl)-l-propanol hydrobromide melts at
141-143C.
Example 19
2-Ethylamino-3-(3,5-dihydroxvphenvl)-1-propanol
hydrobromide
. . .
13.2 g (0.05 mol) of 2-amino-3-(3,5-dihydroxyphenyl)- -
l-propanol hydrochloride are dissolved in 100 ml of
methanol and refluxed for 1 hour after the addition
of 2.2 g (0.05 mol) of acetaldehyde. Subsequently `
the reaction mixture is cooled and after the addition
of 10 g of palladium charcoal (5%) hydrogenated at
5 atmospheres pressure until the uptake of hydrogen
is completed. The catalyst is filtered off with suction
- 35 -
"" ' '
~.. - .

1041548
and evaporated to dryness in vacuo. The residue i8
taken up in dilute hydrobromic acid, filtered over
activated charcoal and the filtrate evaporated to :
dryness in vacuo. By recrystallization from acetonitrile
2-ethylamino-3-(3,5-dihydroxyphenyl)-1-propanol-hydro-
bromide is obtained.
Melting point: 167 - 168C. ~ -
s
- 36 -
.
- '
..

10~1546 . '
Pharmaceutical Composition Examples
Example A ~-
Tablets :
Composition: ~ -
Active ingredient according to the invention
5 parts by weight
stearic acid 6 " " "
glucose 589 " " "
The components are processed in the conventional
way to form tablets each weighing 0.600 g. If desired,
the active ingredient content may be decreased or
increased and the quantity of glucose used increased :
or decreased accordingly. ~.
Example B , :
Suppositories
Composition: . --
. ... ... ... .
2-Amino-3-(3,5-dihydroxyphenyl)-1- '~ : -
propanol hydrobromide20 parts by weight
lactose, pulverized S parts by weight
cocoa butter 1635 parts by weight :~
'. .
- 37 -
, . . .
., ' .,

~04i546
The components are processed in the conventional
way to form suppositories each weighing 1.7 g.
Example C
Capsules
Composition: - -
Active ingredient according to the invention : -
lO parts by weight
lactose 90 " " "
corn starch 400 " " "
The capsules are formulated by carefully mixing
lOOO mg of the finely pulverized components and filled
into hard gelatin capsules.
- 38 -
:' ' ~ , ' . ;
~ - . .
.