Note: Descriptions are shown in the official language in which they were submitted.
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The object of the present invention is a method of
preparing and isolating O-acylsubstituted catecholamine de-
rivatives, i.e. 3,4-diacyloxy-~-~ methylamino)-methy~ -ben-
zylalcohol of the formula
1l
~<--C--O~
R-C- ~ CH-CH2-NH-CH3 (I) . :
wherein R denotes alkyl or aralkyl, preferably tert.~butyl, as
its acid addition salt, preferably as its hydrochloride.
The compounds according to the invention are known ~.
for their sympathomimetic properties and they have been
successfully used i.a. for the treatment of glaucoma. The . :~.
prolonged effect of said compounds compared to the correspond-
ing 3,4-dihydroxy-compound, i.e.-to adrenallne, lS according to :
literature due to the O-acyl protection, which. in the case of
adrenaline prevents the very rapid oxidation in the organism to
compoùnds having no effect.
Irrespective of the protection of the reactive groups,
the acyl compounds of the formula I are not stable under alkal1ne
- conditions, as the hydrolysis of the acyloxy groups is immedi-
ately followed by the formation of oxidation produots. In acid
solutions the said compounds are, however, fairly stable. For ~
the above reasons the amines according to the formula I cannot -
be isolated by means of conventi.onal methods used for preparing ~ .
amines.
. According to methods of preparation of the compounds
of the formula -I described in literature, ortodiacylated cate-
cholamines are treated as salts in alcohol type solvents, such
as methanol or ethanol, whereb~ the afore mentioned disadvanta-
geous phenomena do not occur. In the US patent specifications
3 809 714 and 4 035 405 such a compound is prepared from the
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hydrochloride salt of a compound containing a ke-to function
and having ~he formula II
R-~-O\
R-C-O~ < ~ ~-CH2~NH-CH3 (II)
,
wherein R has the meaning given above, by means of catalytic r
hydrogenation under pressure in methanol or ethanol in the
presence of a platinum oxide catalyst. The produc-t is isola-
ted in a conventional manner by filtering the ca-talyst from
the reaction mixture, evaporating the solvent and crystalli-
zing the compound of the formula I as a productfrom a suitable
solvent mixture.
According to the FI patent specification 55 988 the
compound of the formula I i5 prepared by reducing a compound 1,
of the formula I-II
. j/O
~u ~ CH2 ~ ~ (III)
wherein R has the meaning given above, by means of catalytic
hydrogenation ln an aqueous solvent using palladium on active
charcoal as a catalyst.
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8~(35
These known methods are, however, cumbersome, as
catalytic hydrogenation requires the use of pressure
vessels. There is also always a substantial danger of
self-ignition associated with catalytic hydrogenation.
The method according to the invention for pre-
paring the compounds of the formula I is characterized in
that an acid addition salt of the afore mentioned compound
of the formuIa II is reduced by means of sodium or potassium
borohydride in an acid solvent, preferably acetic acid, and
the acid addition salt of the compound of the formula I is
isolated by adding water to the reaction mix-ture and
extracting the reaction product into a chlorinated hydro-
carbon and treating with the desired acid, preferably
hydrochloric acid.
The reduction according to the invention may
easily be carried out under ordinary condi-tions and using
ordinary vessels thus eliminating the drawbacks associated
with the afore mentioned catalytic hydrogenation.
The reducing effect of the reducing agent depends
on the solvent, wherefore the selection of a proper solvent
for the reduction is important, and glacial acetic acid has
proven to be a very advantageous solvent.
The isolation of the reaction product may easily
be carried out by extracting the same from its aqueous
solution into chlorinated hydrocarbons, such as chloroform
or methylene chloride. The solubility of the product in
chlorinated hydrocarbons is better the larger the group R
is .
According to an advantageous mode of the inven-
tion, the compound of the formula I is prepared by dissol-
ving the hydrochloride salt of the amine of the formula II
into acetic acid and treating with sodium borohydride ,
whereby the temperature is from 0 to 50C and the reaction
time from 1 to 2 hours. The reaction is especially advan-
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tageously performed at or below room temperature (rom 0
to 25C~ whereby the exothermic reaction requires cooling.
The reaction product is isolated by adding water
to the reaction mixture and thereafter extracted, e.g.
into chloroform. Any possibly coex-tracted acetic acid is
washed away from the chloroform e.g. with a sodium bi-
carbonate solution, whereafter the chloroform phase is
treated with diluted hydrochloric acid. From the chloro-
form evaporation residue the hydrochloride of the com-
pound of the formula I is obtained, which can be crystal-
lized from a suitable solvent mixture.
The starting compound of the formula II may be
prepared from adrenalone according to methods known from
literature, e.g. as described in US patent specifications
3 809 714 and 4 035 405.
The following example illustrates the invention.
Example
7.7 g (0.02 moles) of dipivaloyl adrenalone hydro-
chloride is dissolved at room temperature in 50 ml of acetic
acid. Into the reaction mixture is added while cooling and
stirring in the course of half an hour 2.5 g of sodium
borohydride. The reaction mixture is stirred on an ice-
water bath for still one hour, whereafter to the mixture
150 ml of water is carefuliy added. The reaction may be
~followed by means of thin layer chromatography using a
12:3:1-mixture of CH3-NO2, isopropanol and NH3 (95%). The
aqueous solution is extracted with 3 x 50 ml of chloroform,
whereafter the chloroform solution is washed with 50 ml of
a concentrated NaHCO3 solution, 50 ml of 2N hydrochloric
acid and 50 ml of water. The chloroform solution is dried
and evaporated to dryness and the residue, 7.0 g, is crys-
tallized from an acetone-hexane mixture. Yield 5.5 g (71%)
of dipivaloyl-adrenaline hydrochloride, m.p. 158.5-160C
(lit. 159-160C), purity 99.9 % as determined titrimetri-
cally.
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