Note: Descriptions are shown in the official language in which they were submitted.
1053705
The present invention relates to a process for the manufacture of
(L)~ 4-hydroxyphenoxy)-2-hydroxy-3-isopropylamino-propane of the formula
(L)-HO ~ 0-CH2-CH~OH)-CH2-NH-CH(CH3)2 (I)
and pharmaceutically acceptable acid addition salts thereof which comprises
a) separating the (D,L)-racemate of the compound of formula (I) in the form
of a salt with an optically active acid into the diastereomeric salts and
isolating the compound of formula (I) in the form of its diastereomeric salt,
or b) hydrolyzing a compound of the formula
(L)-Zl-O ~ O-CH2-CH(OH)-CH2-NH-CH(CH3)2 (II)
or a salt thereof, wherein Zl represents the ~-D-glucopyranosidyl radical, or
c) hydrogenating a compound of the formula
(L) ~ CH2-0 ~ 0-CH2-CH(OH)-CH2-NH-CH(CH3)2 (III)
or a salt thereof; and when a free compound of the formula (I) is required,
converting a resulting salt into the free compound and when an acid addition
salt is required converting a free compound of the formula (I) into an acid
- addition salt, and when a pharmaceutically acceptable salt is required con-
verting a free compound of the formula (I) into a pharmaceutically acceptable
acid addition salt thereof.
The Fischer projection of formula I has the following appearance:
CH2-0 ~ OH
HO-C-H
CH2-NH-CH(CH3)2
(L)
and corresponds to the (S)-form in the Cahn-Ingold- and Prelog-nomenclature:
CH2- ~ -OH
¦ H
(CH3)2CH-NH_CH ~ ~OH
(S)
- 2 -
1053705
The new compound has valuable pharmacological properties,
particularly an effect on adrenergic B-receptors. It stimulates specifically
cardiac B-receptors. In particular, it has a positively inotropic and
chronotropic action on the isolated vestibule of the heart of the guinea
pig in a concentration range oP fr~m 0.005 to 0.5 ~g/ml, and on the
- 2a -
lOS37Q5
anaesthetised cat in a dosage range of 0.001 to 0.1 mg/kg,
intravenously. As is shown from tests on the anaesthetised
cat, the new compound, however, causes, when administered
in doses which clearly have a positively inotropic and
chronotropic action, no, or only a slight, decrease in
the arterial blood pressure, i.e. it stimulates specifically
the cardiac ~-receptors in comparison with the ~-receptors
in the blood vessels, and consequently clearly differs
~ualitatively from isoproterenol, which strongly stimulates
the ~-receptors of the heart and of the blood vessels.
Since, however, a decrease in blood pressure leads, by
reflex action, to a tachycardia, it can be assumed that
the new compound, when administered to humans in doses
which~have an equally strong positively inotropic action,
produces a tachycardia which is appreciably less than that
caused by isoproterenol.
To be particularly emphasised also is the fact that
the new compound is effective on the anaesthetised cat for
considerably longer than isoproterenol is, and, moreover,
that it produces clear effects also after intraduodenal
adminstration of O.OS mg/kg.
The new compound can hence be used, alone or in
combination with other preparations, such as heart glycosides,
-- 3 --
10537~5
as an agent having a positively inotropic action,
especially for the treatment of myocardial insufficiency.
Administration of the new compound in the form of
suitable pharmacological preparations can be effec~ed
S orally in doses of 1 to 25 mg per single dose, and
'~ .
intravenously in doses of 1 to 20 mcg/kg as a single
dose, or in doses of 0.2 to 2.0 mcg/kgtminute as an
intravenous drip.
(L)-1-(4-hydroxyphenoxy)-2-hydroxy-3-(isopropylamino)-
propane is obtained by processes known per se. Thus, the
new compound can be obtained by a process in which
; (D,L)-1-(4-hydroxyphenoxy)-2-hydroxy-3-(isopropyl-amino)-
propane is split off, and (L)-1-(4-hydroxy-phenoxy)-2-
hydroxy-3-(isopropylamino)-propane is optionally isolated
in the form of a salt. The splitting off and isolation
are performed in a manner known per se. For example, the
racemate can be converted ~Jith salt-forming, optically
active acids, such as organic carboxylic or sulphonic
acids, e.g. the (D)- and (L)-forms of tartaric acid,
di-o-toluyltartaric acid, malic acid, mandelic acid, camphor-
sulphonic acid, quinic acid, lactic acid, glutamic acid
or aspartic acid, into acid addition salts. The resulting
mixtures can, by virtue of physical-cnemical differences,
1053705
e.g. solubility, crystallisability, etc., be separated
into the diastereoisomeric salts and, optionally, the
optically active L-form can be liberated from the salt.
It is also possible to split off the (L)-form from
the racemate by fractional crystallisation from a suitable
solvent, optionally from an optically active solvent,
or by chromatography, especially thin-layer chromatography,
on an optically active carrier substance.
The new compound can be obtained also by the reaction
of a compound of formula II
(L) }~ ~ O_C'32~C.Y_CT~2_Y1 (II)
with a co~pound of formula III
Y2-CH(CH3)2 (III)
wherein one of the radicals Yl and Y2 is amino -NH2
and the other is a reactive esterified hydroxy group, and
Xl represents hydroxy, or Yl together with Xl forms an
epoxy group, whereby in the latter case the absolute
configuration of the epoxide corresponds to the (S)-form
and Y2 is -NH2.
A reactive esterified hydroxyl group is, in particular,
1053705
a hydroxyl ~roup esterified by a strong inorganic or
organic acid, especially a hydrohalic acid such as
hydrochloric acid, hydrobromic acid or hydriodic acid,
also sulphuric acid or a strong organic sulphonic acid
such as a strong aromatic sulphonic acid, for example
benzenesulphonic acid, 4-bromobenzenesulphonic acid or
4-toluenesulphonic acid. Thus, Yl and Y2 stand, in
particular, for chlorine, bromine or iodine.
This reaction is performed in the usual manner. With
the use of a reactive ester as starting material, the process
is carried out preferably in the presence of a basic
condensing agent and/or with an excess of amine. Suitable
basic condensing agents are, for example, alkali hydroxides
such as sodiwn or potassium hydroxide, alkali carbonates
such as potassium carbonate, and alkali alcoholates such
as sodium methylate, potassium ethylate and potassium
tertiary butylate.
Furthermore, the new compound can be obtained by a
process in which in a compound of formula IV
.
2~ (L)~~l-O ~ O-CH2-C~-C}~-N-CH(CH )2 (IV)
wherein at least one of the radicals Zl' Z2 and Z3 stands
-- 6 --
10537Q5
for a group that can be split o~f, and the remaining
radical(s) stand(s).for hydrogen, the group(s) Zl and/or
Z2 and/or Z3 is ~are) split off.
Such radicals that can be split off are, in particular,
radicals that can be split off by solvolysis, reduction,
pyrolysis or fermentation. Radicals that can be split off
by solvolysis are, in particular, radicals that can be
split off by hydrolysis, alcoholysis or acidolysis. Radicals
Zl that can be split off by hydrolysis are, e.g., acyl
radicals, such as optionally functionally modified,
especially esterified, carboxyl groups, such as alkoxy-
carbonyl radicals, e.g. the tert.-butoxycarbonyl radical
or the ethoxycarbonyl radical, aralkoxycarbonyl radicals
such as phenyl-lower-alkoxycarbonyl radicals, e.g. a
carbobenzoxy radical, halocarbonyl radicals, e.g. the
chlorocarbonyl radical, also arylsulphonyl radicals such
as toluenesulphonyl radicals or bromobenzenesulphonyl
radicals, and optionally halogenated, such as fluorinated,
lower alkanoyl radicals, e.g. the formyl, acetyl or
trifluoroacetyl radical, or a benzoyl radical, also those
which together with the oxygen atom form a etherified
hydroxy group, such as sugar radicals, e.g. a l-aldopento-
sidyl radical or a l-aldohexosidyl radical, such as the
...... .
` 1l)5~3705
l-glucopyranosidyl radical, or lower alkyl radicals, e.g.
the methyl or ethyl radical, or lower alkenyl radicals
such as the allyl or methallyl radical, or phenyl-lower-
alkyl radicals, e.g. the benzyl radical.
; 5 Groups Z2 that can be split off by hydrolysis are,
e.g., the groups mentioned above for Zl~ whereby, if Z2
stands for an acyl group, Z3 cannot represent hydrogen.
Groups Z3 that can be split off by hydrolysis are,
for example, acyl radicals, such as the above-mentioned, or
also cyano groups or silyl radicals, such as the trimethyl-
silyl radical. Radicals Z3 that can be split off by
hydrolysis are, besides the mentioned radicals, also doubly
bound radicals, e.g. an alkylidene or benzylidene radical,
or a phosphoranylidene group, such as the triphenylphosphor-
anylidcne group, whereby then the nitrogen atom carries
a positive charge.
Compounds having radicals t,hat can be split off by
hydrolysis are, for example, also compounds of formula V
~S )-Zl ~ 0-CH2 - CH ~ ~ICH~
0\ N - C~(CH~)2 (V)
wherein Zl represen~s hydrogen or has the above-given
-- 8 --
..
1053705
meanings, and Y stands for the carbonyl or thiocarbonyl
radical, or particularly for a bivalent radical Y3 of an
aldehyde or ketone, which radical is theoretically obtainable
by exchange of the oxo group. Ketones Y3 = 0 are, e.g.,
di-lower-alkyl ketones such as methyl ethyl ketone or
acetone. Aldehydes Y3 = 0 are, e.g., lower alkanals such as
acetaldehyde or formaldehyde, also benzaldehyde.
The hydrolysis is performed in the usual manner, e.g.
in the presence of hydrolysing agents, e.g. in the presence
of acid agents, such as an aqueous mineral acid such as
sulphuric acid, or hydrohalic acid such as hydrochloric or
hydrobromic acid, or in the presence of an organic acid, e.g.
a suitable carboxylic acid, such as an a-haloalkanecarboxylic
acid, e.g. of a trifluoro- or chloroacetic acid, of an
organic sulphonic acid, e.g. benzene- or toluenesulphonic acid,
or in the presence of acid ion exchangers, or of basic agents,
e.g. alkali hydroxides, such as sodium hydroxides. Oxy-
carbonyl radicals, arylsulphonyl radicals and cyano groups
can be split off in an advantageo-ls manner by an acid medium
such as a hydrohalic acid. Particularly suitable in this
case is, for example, the splitting-off by means of
aqueous hydrochloric acid, optionally in admixture with
acetic acid. Furthermore, it is possible to split off,
e.g., a tert.-butoxycarbonylradical, under anhydrous
_ 9 _
lOS3~05
conditions, by treatment with a suitable acid, such as
trifluoroacetic acid.
Radicals Zl and/or Z2 and/or Z3 that can be split off
by reduction are, for example, a-arylalkyl radicals
such as benzyl radicals, or a-araikoxycarbonyl radicals
such as benzyloxycarbonyl radicals; these can be split
off in the usual manner by hydrogenolysis, especially by
catalytically activated hydrogen, such as by hydrogen in
the presence of a hydrogenation catalyst, e.g. in the
presence of optionally sulphidised palladium on charcoal,
or ~aney nickel. Further radicals that can be split off
by hydrogenolysis are, for example, 2-halo-alkoxycarbonyl
radicals, such as the 2,2,2-trichloroethoxy-carbonyl
radical or the 2-iodoethoxy- or 2,2,2-tribromoethoxy-
carbonyl radical, which can be split off in the usualmanner, especially by metallic reduction (so-called nascent
hydrogen). Nascent hydrogen can be obtained by the action
of metal or of metal alloys, such as amalgams, on agents
releasing hydrogen, such as carboxylic acids, alcohols or
water, with, in particular, xinc or zinc alloys together
with acetic acid being suitablc. The hydrogenolysis of
2-halo-alkoxycarbonyL radicals can be performed also by use of
chromium(II)-com~ounds, such as chromium(II)-chloride or
, - 10 -
1053705
chromium(II)-acetate. A radical that can be split off by
reduction can also be an arylsulphonyl group, such as the
toluenesulphonyl group, which can be split off in the
usual manner by reduction with nascent hydrogen, e.g.,
by means of an alkali metal, such as lithium or sodium,
in liquid ammonia, particularly from a nitrogen atom.
In carrying out the reduction, it must be ensured that
other reducible groups are not attacked. In the case of
the previously described reaction with catalytically activated
hydrogen using an unsulphidised hydrogenation catalyst,
the procedure is to be carried out, in particular, at low
temperature, e.g. between -50 and +50C, preferably at
between 0 and 25C.
Radicals Zl and/or Z2 and/or Z3 that can be split off
by pyr~lysis are, for example, optionally substituted,
pàrticularly however unsubstituted, carbamoyl groups.
Suitable substituents are, e.g~, lower alkyl or aryl-lower-
alkyl, such as methyl or benzyl, or also aryl, such as phenyl.
The pyrolysis is performed in the usual malmer, with
allowance being made for other thermally sensitive groups.
Radicals Zl and/or Z2 and/or Z3 that can be split off by
fermentation are, for example, optionally substituted,
particularly however unsubstituted, carbamoyl groups.
- 11 -
.
1053705
Suitable substituents are, e.g., lower alkyl or aryl-
lower-alkyl, such as methyl or benzyl, also aryl, such
as phenyl. The fermentation is performed in the usual
manner, e.g. by means of enzme urease or soya bean
extracts, or glucosidase, at about 20C or at slightly
elevated temperature.
In addition, the new compound can be obtained using
a procedure whereby in a compound derived from the new
compound, in which derived compound the nitrogen atom
is bound to one of its substituents by a double bond,
the -C=N-double bond is reduced.
Thus, a Schiff base of formula VI
0~ '
(S)-~0 ~ -o-~H2-cH-cr~ c~l(cH3)2 (VI),
or of formula VII
(L)-R0 ~ 0-CR2-CR-C'~2-~=C(C~)2 (VII),
or a ring tautomer,corresponding to formula VII, of
formula VIII (S!-H0 ~ 0-C~l2-lc~ _ ICH2
- 0\ N-~l
/ C \ (VIII),
CH~ CH3
- 12 -
~ 053705
whereby compounds of formulae VII and VIII can also be
present together, can be reduced.
This reduction is performed in the usual manner, for
example, with a di-light metal-hydride, such as sodium
boron hydride or lithium aluminium hydride, or with a
hydride, such as borane or formic acid. It is advantageous
to use mild reducing agents such as, in particular, alkali
metal boron hydrides, e.g. sodium boron hydride or,
preferably, sodium cyanoboron hydride, and to operate under
mild conditions, e.g. at normal or moderately elevated
temperature, and in an inert solvent, such as alkanol,
e.g. in ethanol or methanol, or ether, e.g. in diethyl
ether, tetrahydrofuran or dioxane, or in water.
` Depending on the process conditions and starting
materials, the final material is obtained in the free form,
or in the form, likewise included in the invention, of
its acid addition salts. It is thus possible to obtain,
for example, basic, neutral or mixed salts, optionally also
hemi-, mono-, sesqui- or polyhydrates thereof. The acid
addition salts of the new compound can be converted, in a
manner kno~n per se, into the free compound, e.g. with
basic agents, such as alkalis or ion exchangers. On the
other hand, the resulting free base can form salts with
- 13 -
. .
1053705
organic or inorganic acids. For the preparation of acid
addition salts, there are used, in particular, those acids
which are suitable for the obtainment of therapeutically
applicable salts. Such acids are, for example: hydrochloric
acid, hydrobromic acids, sulphuric acids, phosphoric acids,
nitric acid, fumaric acid, aliphatic, alicyclic, aromatic
or heterocyclic carboxylic or sulphonic acids, such as
formic, acetic, propionic, succinic, glycolic, lactic,
malic, tartaric, citric, ascorbic, maleic, pyruvic,
benzoic, anthranilic, p-hydroxybenzoic, salicyclic, pamoic,
methanesulphonic, ethanesulphonic, hydroxyethanesulphonic,
ethylenesulphonic, halobenzenesulphonic, toluenesulphonic,
cyclohexylaminosulphonic or sulphaDilic acid.
These or other salts of the new compound, such as
picrate, can also serve for purification of the free base
obtained, in that the free base is converted into its salt,
this is separated, and the base is then liberated from
the sa]t. In consequence of the close relationship between
the new compound in the free form and in the form of its
salts, it is to be taken, in the foregoing and in the
follow;ng, that by the term 'free compound' are meant, where
the case applies and with the appropriate modifications,
also the corresponding salts.
- 14 -
1053705
The invention relates also to those modifications ofthe process whereby a compound occurring as an intermediate at
some stage of the process is used as starting material, and the
uncompleted steps are performed, or whereby the process
S is interrupted at some stage, or whereby a starting
material is formed under the reaction conditions, or
whereby a reaction constituent is optionally present in
the form of its salts.
- Thus, a compound of formula II wherein Xl represents
hydroxy, and Yl stands for -NH2, can be reacted in a suitable
manner with acetone in the presence of a suitable
reducing agent, such as one of ~he above-mentioned. As
intermediate, there is obtained a compound of formula VII
or VIII, which is then reduced according to the invention.
The starting ma~erials are known or, if they are neu,
can be obtained by methods kno~n per se.
Starting materials of formula II wherein Xl represents
hydroxy, and Yl stands for a reactive esterified hydroxy
group, or Yl together with Xl forms an epoxy group, can
be obtained by, for example, a process in which a compou~d
of formula IX
Zl 0 ~ OH
. (IX),
- 15 -
~ 053705
wherein Zl has the above meanings and can be split off
by solvolysis, reduction, pyrolysis or fermentation,
is reacted with a compound of formula X
1 1 (X)
wherein Xl and Yl have the above meanings and preferably
together stand for epoxy, and A is a reactive esterified
hydroxy group, e.g. the above-mentioned hydroxy group,
to give a compound of formula XI
(L)-Zl- ~ o-c~2-cH-c~l2-yl (XI),
and the group Zl is subsequently a~ain split off in the
intended manner.
Compounds of formula IV wherein Zl stands for a group
that can be split off~ Z2 represents hydrogen, and Z3 stands
for hydrogen or for a group that can be split off, can
be obtained by, for example, a process in ~hich a compound
of formula XIa
OH
(D,L)_zl_o ~ O-CH2-CH-CH2yl (XIa)
wherein Zl has the above meaning and Y is a reactive
- 16 -
~05370S
esterified hydroxy group, is reacted in the usual manner
with a compound of formula XII
, ~ .
HN-c~l(c~i3)2 (XII)
wherein Z3 has the above-given meanings or stands for
hydrogen; and the L-form is then split off from the
racemate, e.g. by one of the aforementioned methods.
Compounds of formula IV wherein Zl stands for a group
that can be split off~ Z2 represents hydrogen, and Z3
stands for hydrogen or for a group that can be split off,
can be obtained also by reacting in the usual manner
a compound o formula XIII
X~
¦ 1~ (XIII~
(L)~A-c~2-c~I-c}I2-~-cH(c~3)2
wherein A is reactive esterified hydroxy, and Xl is hydroxy,
or A and Xl together are epoxy; or, if Z3 is hydrogen,
A together with the hydrogen atom of the amino group can
also be a direct bond.
Starting materials of formula V wherein Zl and Y have
the given meanings can be obtained, for example, by
reacting in the usual manner a compound of formula IX
- 17 -
~0537~5
- with a compound of formula XIIIa
,
(S)-A-CH2-CH I 2
O\ ~ - CH(CH~)2 (XIIIa)
y ,.
wherein Y has the given meanings, and A stands for a
. reactive esterified hydroxy group~ e.g. for the above-
mentioned one.
: Compounds of formula VI and VII can be produced by,
for example, a process in which a compound of formula IX
wherein Zl is preferably a group that can be split off
by solvolysis, pyrolysis or fermentation, and has the
corresponding above-given meanings, is reacted, in the
usual manner, with a compound of formula XIV
Xl '
(S ~-A-CH2-CH-CH=N-CH(CH~)2 (XIV),
or with.a compound of formula XV
(S)-A-C~2-C~-CH2-N=C~CH3)2 (XV)
wherein Xl represents hydroxy, and A stands for a reactive
- 18 -
1053705
esteriied hydroxy group, e.g. for the above-given one,
or wherein A and Xl together form an epoxy group; and
subsequently the group Zl that can be split o~f by
solvolysis, pyrolysis or fermentation is split off, e.g.,
in the above-described manner.
The new compound can be used as a pharmaceutical
active substance, e.g., in the form of pharmaceutical
preparations which contain the new compound, or its salts,
in admixture with a pharmaceutical, organic, solid or
liquid carrier material that is suitable, for example,
for enteral, e.g. oral, administration or for parenteral
administration. For the formation of this carrier material,
suitflble substances are ones which do not react with the
new compound, such as water, gelatine, lactose, starch,
lS magnesium stearate, talcum, vegetable oils, benzyl
alcohols, gum, polyalkylene glycols, vaseline, cholesterol
or other known carriers for pharmaceutical active substances.
The pharmaceutical preparations can be in the form o,
for example, tablets, dragées, capsules, suppositories,
ointments or creams, or they can be in liquid form as
solutions (e.g. as elixir or syrup), suspensions or
emulsions. They are optionally sterilised and/or contain
auxiliaries, such as preservatives, stabilisers, wetting
or emulsifying agents, salts for regulation of the osmotic
- 19 -
1053705
pressure, or buffers. They may also contain other
therapeutically valuable substances. These preparations,
which can also be used in veterinary medicine, are
manufactured by the customary methods. The daily dose
for a warm-blooded animal of about 75 kg body weight
is approx. 10-100 mg per os, preferabLy approx. 20-40 mg
per os.
The following examples illustrate the invention
without however limiting the scope thereof. The temperature
values are given in degrees Centigrade.
- 20 -
.. ,, , . . ~,~ .. ~
1053705
Example 1
4.5 g of (~ (4-hydroxyphenoxy)-2-hydroxy-3-(isopropyl-
amino)-propane is dissolved in 30 ml of methanol, and a
solution of 8.1 g of (~)-di-0,0'-p-toluoyl-D-tartaric
acid in 25 ml of methanol and 25 ml of water is added.
The solution is then concentrated at room temperature in
a water-jet vacuum until commencement of a slight clouding,
and subsequently, to allow crystallisation, left to stand
at 0 for 15 hours. The precipitated crystals are filtered
off with suction, and subsequently recrystallised twice
from methanol/water l:l to obtain 3.7 g of (-)-1-(4-
hydroxyphenoxy)-2-hydroxy-3-(isopropyl-amino)-propane-
(~)-di-0,0'-p-toluoyl-D-hydrogen tartrate, M.P. 134-137.
For isolation of the free enantiomeric base, the salt
is taken up in 2N hydrochloric acid, and extracted by shaking
with ethyl acetate. (~)-Di-0,0'-p-toluoyl-D-tartaric acid
can be regenerated from this extract. The acid solution
is rendered alkaline with concentrated ammonia, saturated
with sodium chloride and extracted by shaking with ethyl
acetate. The organic phase is washed with brine, dried over
sodium sulphate and concentrated in a water-jet vacuum.
The residue crystallises from ethyl acetate. lhere is
obtained 1.0 g of pure (-)-1-(4-hydroxyphenoxy)-2-hydroxy-
- 21 -
1053705
3-(isopropylamino)-propane, M.P. 129-130~. [alD: -0.9 -
0.5 (1% solution in methanol). The neutral fumarate
prepared therefrom crystallises from methanol/ether,
M~Po 210-211~ ~a~D -21~5 ~ 0~5 (1% solution in
methanol).
~ 22 ~
.
~053705
Example 2
6.o g of the diastereoisomer of l-~p-(~-D-glucopyrano-
sidyloxy)-phenoxy]-3-isopropylamino-2-propanol, M.P. 157-
160/186-187, is dissolved in 20 ml of 2N sulphuric acid,
and the solution is heated for 3 hours at 80. The reaction
mixture is then cooled, made alkaline with concentrated
ammonia, saturated with sodium chloride and extracted with
ethyl acetate. The ethyl acetate extract is dried with sodium
sulphate and concentrated in a water-jet vacuum. The residue
crystallises from ethyl acetate. There is obtained 2.0 g of
(-)-1-(4-hydroxy-phenoxy)-2-hydroxy-3-(isopropylamino)-
propane, l12: -0.9 ~ 0.5 (C = 1.0% g/v in methanol). The
neutral fumarate prepared therefrom with fumaric acid
- crystallises from methanol/ether, M.P. 210-211, I]D: -21.5
~ 0.5 (C = 1.01% g/v in methanol).
15The starting material required for this reaction can
be produced as follows:
27.2 g (0.1 mole) of hydroquinone-~-gluco-pyranoside
and 250 ml of epichlorohydrin are dissolved in 1.0 litre of
ethanol; 6.9 g (0.05 mole) of potassium carbonate is added
and the whole is refluxed for 6 hours. The resulting
precipitate is filtered off with suction, and the filtrate
is concentrated in a water-jet vacuum. The residue is
dissolved in ethanol and filtered. The filtrate is cooled
and ether is added until clouding co~nences. The precipitated
- 23 -
~0537(~5
reaction product is filtered off with suction and washed
with ether. There is thus obtained 4-(2,3-epoxy-propoxy)-
phenyl-~-D-glucopyranoside as a mixture of the two
possible diastereomers.
25 g of t:his diastereomer mixture is dissolved in
300 ml of methanol, and the solution is refluxed with
18.5 g of isopropylamine for 6 hours. The reaction mixture
is subsequently completely concentrated by evaporation.
The residue is dissolved in 35 ml of water, and 11.6 g
of cyclohexylsulphamic acid dissolved in acetone is added.
Acetone is added to this solution until clouding commences.
The reaction products begins to precipitate in crystalline
form. To allow completion of crystallisation, the whole is
left to stand at 0 for 15 hours. The precipitated crystals
are filtered off with suction and recrystallised from
acetone/water. They yield the diastereomer that is not
required for the further operation.
The mother liquors occurring during the crystallisation
process are combined, and concentrated in a water-jet vacuum
to a syrup, which is dissolved in 50 ml of water. This
solution is filtered through a column having 200 ml of
Amberlite I~A-400 ~ (strongly basic ion exchanger having
trimethylammonium groups [particle size C.38 - 0.45 mm]).
- 24 -
1053705
The column is washed with water until th~ liberated base
is completely eluted. The combined aqueous eluates are
completely concentrated in a water-jet vacuum, and
recrystallised three times from methanol/isopropanol.
There is obtained the second diastereomer of l-[p-
(~-D-glucopyranosidyloxy)-phenoxy~-3-isopropyl-amino-2-
propanol, M.P. 157-160 / 186-189.
- 25 -
1053705
- Example 3
Tablets containing 20 mg of active substance are
produced, in the normal manner, with the following
composition:
Composition
(~ (4-hydroxyphenoxy)-2-hydroxy-
3-(isopropylamino)-propane 10 mg
wheat starch 60 mg
lactose 50 mg
colloidal silicic acid S mg
talcum ~ mg
magnesium stearate 1 m~
135 mg
Preparation
(-)-1-(4-Hydroxyphenoxy)-2-hydroxy-3-(isopropylamino)-
propane is mixed with a portion of the wheat starch, with
lactose and colloidal silicic acid, and the mixture is
put through a sieve. A further portion of the wheat starch
is made into a paste with the 5-fold amount of water on a
water bath, and the powder mixture is kneaded with the
paste until a slightly plastic mixture is formed.
The p]astic mixture is pressed through a sieve of approx.
3 mm mesh size; it is dried and the resulting dry granulate
is again put through a sieve. The remaining wheat starch and
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- 1053705
~he talcum and magnesium stearate are then mixed in
and the mixture is pressed to obtain tablets each
weighing 135 mg and having a cross-groove.
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1053705
Example 4
a) A solution of 1.6 g of 1-isopropylamino-2S-hydroxy-3-
(4-benzyloxy-phenoxy)-propane-hydrochloride in 160 ml of
ethanol is hydrogenated with 0.2 g Gf 5% palladium on
charcoal under normal pressure. After absorption of the
calculated amount of hydrogen, the catalyst is ~iltered
off, and the solution is concentrated by evaporation to
dryness. The residue is dissolved in 45.6 ml of O.lN
sodium hydroxide solution, and the solution is extracted
with ethyl acetate. After drying by means of magnesium
sulphate, the organic phase is concentrated by evaporation,
and the residue is recrystallised from ethyl acetate to
obtain l-isopropylamino-2S-hydroxy-3-(4-hydroxy-phenoxy)-
propane, M.P. 127-128; [a]D = -1 ~ 1; [a]Hg z 2 + 1
(methanol, c = 0.940).
9.1 ml of a 4% solution of fumaric acid in methanol
is added to a solution of 0.7 g of the resulting l-isopropyl-
amino-2~-hydroxy-3-(4-hydroxy phenoxy)-propane in 5 ml
of methanol. Ether is added thereto until clouding commences
and the solution is then cooled. The fo-rmed crystals are
filtered off ~7ith suction and dried: they constitute
l-isopropylamino-2S-hydroxy-3-(4-hydro~y-phenoxy)-propane -
1/2 fumarate; M.P. 209-211; [a]20 = -23 + l~;
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lOS3705
la~Hg = -68 + 1 (methanol, c - 1.061).
The starting material can be produced as follows:
b) A few drops of pyridine are added to a melt, heated
to 120, of 100 g of 5,6-anhydro-1,2-0-isopropylidene-a-
D-glucofuranose and 100 g of hydroquinonemonobenzyl ether,
with the internal temperature being maintained at below
140 by means of external cooling with lukewarm water. After
the exotherrnic reaction has subsided, the reaction mixture
is stirred for a further 30 minutes at 140, and then
cooled to 80; 500 ml of methanol is added and subsequently
water until clouding commences. After several hours'
standing at 0, the precipitated crystals are filtered off
with suction and recrystallised from methanol to obtain
1,2-0-isopropylidene-6-0-(4-benzyloxyphenyl)-a-D-gluco-
furanose; M.P. 99-102; Rf-value = 0.25 on silica gel
thin-layer plates in the system methylene chloride :
methanol 15:1.
c) 500 ml of water is added dropwise, with stirring, to
a solution, heated to 70, of 127.3 g of 1,2-0-isopropylidene-
6-0-(4-benzyloxy-phenyl)-a-D-glucofuranose in 800 ml of
glacial acetic acid; the whole is further stirred for
14 hours at 70, and subsequently concentrated in a water-
jet vacuum to dryness. The crystalline residue is then
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10537~5
recrystallised from 1 litre of glacial acetic acid
to obtain 6-0-(4-benzyloxy-phenyl)-D-glucose; M.P. 164-
168; Rf-value = 0.61 on silica gel thin -layer plates
with methanol; [a]20 = -62 + 1 (methanol, c = 0.985).
d) 64 g of sodium metaperiodate is added portionwise,
with stirring and external cooling, in the course of 15
minutes to a suspension of 36.2 g of the resulting
6-0-(4-benzyloxyphenyl)-D-glucose in a mixture of 600 ml
of methanol, 10 ml of glacial acetic acid and 60 ml of
water, and the whole is stirred at about 25 for 20 hours.
The insoluble material is filtered off and the filtrate
is concentrated by evaporation to dryness; the residue is
taken up in chloroform, this solution is washed with
water and dried by means of magnesium sulphate, and the
solvent is evaporated off in a water-jet vacuum. The
residue is dissolved in 150 ml of methanol, and the solution
is added dropwise, during 45 minutes, to a solution,
cooled to -5, of 3.8 g of sodium boron hydride in 150 ml
of methanol and 40 ml of water. After standing for a further
15 hours at about 25, the reaction mixture is concentrated
by evaporation to dryness; the residue is taken up in
chloroform, the solution is washed with ice-cold 2N
hydrochloric acid and water and, after drying by means of
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1053705
magnesium sulphate, the solvent is evaporated off in
a water-jet vacuum. The residue is recrystallised from
chloroform to obtain 1-(4-benæyloxyphenoxy)-2S,3-dihydroxy-
propane; M.P. 134-138; Rf-value = 0.32 on silica gel
thin-layer plates in the system methylene chloride:
methanol 15:1.
e) A solution of 5.7 g of p-tosyl chloride in 30 ml of
pyridine is added dropwise in the course of 4 hours,
with stirring and with the exclusion of moisture, to a
solution, cooled to -10, of 8.2 g of the resulting
1-(4-benæyloxy-phenoxy)-2S,3-dihydroxy-propane in 20 ml
of pyridine, and the whole is allowed to stand at about
25 for 16 hours. The reaction mixture is diluted with
chloroform and ~ater; the separated organic phase is washed
with ice-cold 2N hydrochloric acid, with water, with a
saturated sodium hydrogen carbonate solution and, finallv,
again with water; it is dried by means of magnesium sulphate
and the solvent is removed. The residue is purified by
column chro~atography on 250 g of silica gel with a mixture
of methylene chloride/ethyl acetate 19:1, and the product
is recrystallised from an ethyl acetate/petroleum ether
mixture to obtain 1-(4-benzyloxy-phenoxy)-2R-hydroxy-3-p-
tosyloxy-propane; ~I.P. 70-74; Rf-value = 0.36 on solica gel
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1053705
thin-layer plates in the system methylene chloride/ethyl
acetate 19:1; [a]D = ll + 1 (chloroform, c = 1.631).
f) A solution of 3.8 g of 1-(4-benzyloxy-phenoxy)-2R-
hydroxy-3-p-tosyloxy-propane in 40 ml of ethano~ and 4 ml
of isopropylamine is maintained for 30 hours at a
temperature of 50, and subsequently concentrated by
evaporation to dryness. The residue is taken up in
methylene chloride, the solution is washed with 2N sodium
hydroxide solution and then with water, it is dried by
means of magnesium sulphate, and the solvent is distilled
off to obtain l-isopropylamino-2S-hydroxy-3-(4-benzyloxy-
phenoxy)-propane, which is recrystallised from methylene
chloride/petroleum ether; M.P. 91-93.
This compound is dissolved in a small arnount of ethanol,
and alcoholic hydrochloric acid is added until the pH is 4;
ether is then added until cloudiness commences. After
cooling, there crystallises out l-isopropylamino-2S-hydroxy-
3-(4-benzyloxy-phenoxy)-propane-hydrochloride, which is
filtered off with suction and dried; M.P. 161-163;
la]20 = -19 ~ 1; la]Hg = _57o + 1 (methanol: c = 4.9~3)-
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