Process of producing the magnesium salt of p-chlorophenoxyisobutyric acid

P-chlorophenoxyisobutyric acid is dissolved in an aqueous solution of a surplus of ammonia. The resulting solution is reacted with an aqueous solution of a magnesium salt, which latter solution contains a large surplus of ammonium ions and gaseous ammonia.

This invention relates to a process of producing the magnesium salt of 
p-chlorophenoxyisobutyric acid having the formula 
##STR1## 
The magnesium salt of p-chlorophenoxyisobutyric acid is known, e.g., from 
Austrian Patent Specification No. 265,243 and German Opened Specification 
No. 2,308,331. In Austrian Patent Specification No. 265,243 it is proposed 
to produce the magnesium salt of p-chlorophenoxyisobutyric acid in that a 
magnesium compound, e.g., the acetate, the basic carbonate or the 
hydroxide, is reacted with p-chlorophenoxyisobutyric acid in an aqueous 
medium. In Opened German Specification No. 2,308,331 it is similarly 
suggested to cause magnesium compounds, such as magnesium sulfate or 
magnesium chloride, to react with p-chlorophenoxyisobutyric acid in the 
presence of sodium hydroxide in that the magnesium salt is stirred into a 
solution which contains the sodium salt of p-chlorophenoxyisobutyric acid. 
Both known processes have the disadvantage that inexpensive magnesium 
compounds, such as magnesia, magnesium hydroxide and basic magnesium 
carbonate, are virtually insoluble in water so that only a slow reaction 
can be effected in an aqueous medium as the reaction takes place in a 
heterogeneous medium. 
Another disadvantage of the known processes resides in that 
p-chlorophenoxyisobutyric acid must be transformed to its sodium salt. 
This is very difficult in practice because it is not simple to adjust 
exactly equivalent conditions for this neutralizing reaction. Magnesium 
salts must then be added also in an exactly equivalent quantity in order 
to avoid a surplus or deficiency of extraneous ions. For instance, in the 
process described in Opened German Specification No. 2,308,331, magnesium 
salt must be gradually added with stirring, and the acid and sodium 
hydroxide must be present in exactly stoichiometric proportions because 
any surplus sodium hydroxide would immediately cause the precipitation of 
the fed magnesium as magnesium hydroxide. In the known process it is 
highly expensive to separate the desired magnesium salt of 
p-chlorophenoxyisobutyric acid from the extraneous ions and the resulting 
product must be very thoroughly washed. It is apparent that the known 
processes are highly expensive and must be very exactly controlled. For 
these reasons, they have not been successful in practice. 
The magnesium salt of p-chlorophenoxyisobutyric acid is a compound which is 
highly interesting for pharmaceutical purposes and which is superior in 
hypolipemic properties to the known other preparations based on 
p-chlorophenoxyisobutyric acid. The magnesium compound of 
p-chlorophenoxyisobutyric acid is superior to the free acid or the ethyl 
ester in use because it has improved compatibility after oral 
administration. Besides, magnesium is an essential component of tissues 
and body fluids and is of high physiological significance. The 
physiological significance of magnesium ions becomes apparent, e.g., in 
numerous metabolic reactions because the activity of the enzymes depends 
on certain ions. When magnesium ions are supplied in the form of the 
magnesium compound of p-chlorophenoxyisobutyric acid to the organism which 
suffers from hyperlipidemia, these magnesium ions very considerably 
increase the activity of p-chlorophenoxyisobutyric acid. When an increased 
decomposition of the lipoproteides present in the circulatory system has 
been initiated by p-chlorophenoxyisobutyric acid, that decomposition is 
promoted by the presence of magnesium or magnesium ions and this presence 
does not adversely affect the inhibiting activity of 
p-chlorophenoxyisobutyric acid on the hepatic biosynthesis of cholesterin 
during the conversion of acetyl-coenzyme A to mevalonic acid and on the 
synthesis of fatty acid at the rate-controlling stage by an inhibition of 
the acetyl-coenzyme A-carboxylase. 
It is apparent that there is a considerable desire for a process which 
enables a simple production of the magnesium salt of 
p-chlorophenoxyisobutyric acid in high yields from substances which can be 
commercially mass-produced. 
This object is accomplished according to the invention by the provision of 
a process in which p-chlorophenoxyisobutyric acid having the formula 
##STR2## 
or a salt of such acid is dissolved in an aqueous solution of a surplus of 
ammonia and the resulting solution is mixed with an aqueous solution of a 
magnesium-ammonium salt solution. The dissolving of magnesia, magnesium 
hydroxide or basic magnesium carbonate in a solution of a surplus of an 
ammonium salt results in an aqueous solution of a magnesium salt, 
preferably magnesium chloride, and that aqueous solution contains, in 
accordance with the invention, a large surplus of ammonium ions and 
gaseous ammonia. 
The reaction in an aqueous medium in the presence of ammonium ions and 
gaseous ammonia ensures that the magnesium compounds which are used will 
be in solution even under alkaline conditions so that the reaction is 
effected in a homogeneous medium. Besides, an exact control of the 
quantities in which the starting compounds are used is no longer required 
because both starting compounds are in solution and the presence of 
ammonium ions and gaseous ammonia causes the magnesium salt of 
p-chlorophenoxyisobutyric acid to precipitate as a crystalline substance 
of very high purity and even the use of a surplus of the magnesium 
compound is by no means disturbing. In the process according to the 
invention, the reaction takes place in a homogeneous medium so that there 
can be no phase boundary transitions which could adversely affect the 
yield. 
A further advantage resides in that the ammonium salt-containing solution 
which is available after the separation of the desired magnesium salt can 
be re-used so that there are virtually no losses of ammonium salt. 
The reactive derivatives of p-chlorophenoxyisobutyric acid which may be 
used include the salts of the acid, e.g., the sodium or ammonium salt. 
The magnesium compounds which can be used include mainly magnesia, 
magnesium hydroxide and basic magnesium carbonate, although magnesium 
salts of organic acids, such as magnesium acetate or alcoholates, e.g., 
magnesium ethylate or the like, may also be used with good success. 
Because the process according to the invention permits of a use of 
magnesium compounds which are insoluble or only difficultly soluble in 
pure water, it is possible to use magnesium compounds, such as magnesia, 
magnesium hydroxide or basic magnesium carbonate, in which magnesium is 
available at lower cost than in the magnesium compounds mentioned in 
Opened German Specification No. 2,308,331. For instance, magnesia contains 
60% by weight of magnesium, i.e. a higher percentage of magnesium than all 
other magnesium compounds.

Some examples of the process according to the invention will now be 
described: 
EXAMPLE 1 
34 g (about 0.6 mole) ammonium chloride were dissolved in 100 g 
demineralized water with stirring. 4.4 g (0.11 mole) magnesia was stirred 
into the resulting solution, which was heated to the boil with reflux 
cooling for 30 minutes. This resulted in the formation of a solution with 
release of ammonia gas. The solution was filtered. 
20 g demineralized water was added to 42.9 g (0.20 mole) 
p-chlorophenoxyisobutyric acid. The addition of 22 g concentrated aqueous 
ammonia solution (24 to 26% concentration) with stirring resulted in a 
clear solution. 
When the magnesium-containing solution was stirred into the acid-containing 
solution, the magnesium salt of p-chlorophenoxyisobutyric acid immediately 
began to settle as an initially resinous substance, which rapidly 
crystallized when stirred. The resulting mixture was placed into a 
refrigerator to complete the crystallization. 47.8 g of moist crystals, 
which smelled of ammonia, were recovered when the liquid was sucked off 
and were dried at 120.degree. C. for 14 hours. The resulting product 
consisted of the purely white magnesium salt of p-chlorophenoxyisobutyric 
acid, melting point 318.degree.-321.degree. C., which is obtained in a 
yield of virtually 100%. 
EXAMPLE 2 
34 g (about 0.6 mole) ammonium chloride were dissolved in 100 g 
demineralized water and 4 g (0.1 mole) magnesia was stirred into the 
solution. The resulting mixture was boiled with reflux cooling for 30 
minutes until a clear solution was available, which was filtered when 
cold. 
60 g demineralized water were added to 43 g (about 0.2 mole) 
p-chlorophenoxyisobutyric acid and 26 g concentrated aqueous ammonia 
solution (24 to 26% concentration) were added. The resulting mixture was 
stirred until the soluble substances had been completely dissolved. The 
solution was filtered too. 
When the magnesium-containing solution was stirred into the acid-containing 
solution, a paste was formed and this was immediately succeeded by the 
crystallization of the magnesium salt. To complete the crystallization, 
the reaction mixture was kept in a refrigerator over night. Liquid was 
sucked from the crystals. When they had been dried at 60.degree. for 6 
hours, 49 g of the tetrahydrate of the magnesium salt of 
p-chlorophenoxyisobutyric acid, melting point above 300.degree. C., were 
obtained. When the tetrahydrate was subsequently dried at 120.degree. C. 
for 15 hours, 42 g of the anhydrous magnesium salt of 
p-chlorophenoxyisobutyric acid (yield 93%), melting point 
320.degree.-322.degree. C., were obtained. 
EXAMPLE 3 
40 g ammonium chloride were dissolved in 100 g demineralized water with 
gentle heating. 4.4 g (0.11 mole) magnesia were stirred into the resulting 
solution. When the resulting mixture was heated to the boil with reflux 
cooling for 15 minutes, ammonia gas was released and a slightly turbid 
solution was obtained. When the solution was filtered, a clear filtrate 
became available. 
42.9 g (0.20 mole) p-chlorophenoxyisobutyric acid and 20 g demineralized 
water were stirred together. 20 g aqueous concentrated ammonia solution 
(24 to 26% concentration) were then stirred in. The magnesium-containing 
solution was stirred into the resulting solution so that the latter became 
turbid and a resinous substance settled and subsequently crystallized when 
stirred. The reaction mixture was kept in a refrigerator over night to 
complete the crystallization. Liquid was sucked and thoroughly pressed 
from the crystals. When the latter were dried, the weight was constant 
after about 2 hours. After the crystals had been dried for a total of 20 
hours, 43.8 g of the magnesium salt of p-chlorophenoxyisobutyric acid 
(yield 97%) were obtained in the form of pale yellow crystals having a 
melting point of 318.degree.-320.degree. C. 
EXAMPLE 4 
40 g ammonium chloride were dissolved in 100 g demineralized water with 
gentle heating. 4.4 g (0.11 mole) magnesia were stirred into the resulting 
solution. When the resulting mixture was heated to the boil with reflux 
cooling for 15 minutes, a slightly turbid solution was obtained, which was 
then filtered. 
42.9 g (0.20 mole) p-chlorophenoxyisobutyric acid were dissolved in 60 g 
aqueous ammonia solution (10% concentration) and the resulting solution 
was filtered. When the magnesium-containing solution made as described 
hereinbefore was stirred into the acid solution, the latter became turbid 
and a resinous substance settled, which crystallized when stirred. The 
reaction mixture was kept in a refrigerator over night. Thereafter, liquid 
was sucked and pressed from the crystals, which were subsequently washed 
with 15 ml demineralized water and then dried at 120.degree. C. for 2 
hours. 42.26 g of the magnesium salt of p-chlorophenoxyisobutyric acid 
(yield 93.6%) were obtained in the form of white crystals having a melting 
point of 322.degree.-325.degree. C. 
EXAMPLE 5 
50 g ammonium chloride were dissolved in 140 g demineralized water with 
heating. 4.4 g (0.11 mole) magnesium oxide were stirred into the resulting 
solution. When the resulting mixture was heated to the boil with reflux 
cooling for 30 minutes, ammonia gas was released and a yellowish solution 
was obtained, which was filtered. The filtrate was clear and colorless. 
42.9 g (0.20 mole) p-chlorophenoxyisobutyric acid were dissolved in 60 g 
aqueous ammonia solution (10% concentration). The resulting solution was 
filtered. 
When the magnesium-containing solution was heated to 80.degree. C. and was 
then stirred into the acid-containing solution, crystals were precipitated 
immediately. The mixture was cooled to 20.degree. C. and was stirred. 
Liquid was sucked and thoroughly pressed from the crystals, which were 
then dried at 120.degree. C. for 11/4 hours. 44.64 g of the magnesium salt 
of p-chlorophenoxyisobutyric acid (98.8% yield) were obtained in the form 
of white crystals havng a melting point of 318.degree.-322.degree. C. 
EXAMPLE 6 
30 g (about 0.6 mole) ammonium chloride were dissolved in 140 g aqueous 
ammonia solution (10% concentration). 21 g (about 0.105 mole) magnesium 
chloride (MgCl.sub.2.6H.sub.2 O) were dissolved in the resulting solution 
with stirring. The resulting solution was filtered. 
43 g (about 0.2 mole) p-chlorophenoxyisobutyric acid were charged into 60 g 
demineralized water. 26 g concentrated ammonia solution (24 to 26% 
concentration) were added to the mixture, which was stirred until all 
soluble matter had been dissolved. When the magnesium-chloride solution 
was stirred into the acid-containing solution, a paste was formed and the 
magnesium salt of p-chlorophenoxyisobutyric acid began to crystallize 
immediately. The reaction mixture was kept in a refrigerator over night to 
complete the crystallization. Liquid was then sucked from the precipitated 
crystals, which were subsequently dried for about 4 hours at 60.degree.. 
45 grams of the tetrahydrate of the magnesium salt of 
p-chlorophenoxyisobutyric acid were thus obtained. When the tetrahydrate 
was dried at 120.degree. C. for 15 hours, 38.2 g anhydrous magnesium salt 
of p-chlorophenoxyisobutyric acid (yield 84.5%) having a melting point of 
319.degree.-322.degree. C. were obtained. 
EXAMPLE 7 
35 g (about 0.65 mole) ammonium chloride were dissolved with stirring in 
100 g demineralized water. 6.4 g (about 0.11 mole) magnesium hydroxide 
were stirred into the resulting solution. When the resulting mixture was 
heated to the boil with reflux cooling for 30 minutes, a colorless 
solution formed and ammonia gas was released. When the solution was 
filtered, a clear filtrate was obtained. 
42.9 g (0.20 mole) p-chlorophenoxyisobutyric acid were dissolved in 60 g 
aqueous ammonia solution (10% concentration). The solution was filtered. 
When the magnesium-containing solution was stirred into the filtrate, the 
latter became turbid and a resinous substance separated, which 
crystallized when stirred. The reaction mixture was kept in a refrigerator 
over night to complete the crystallization. Liquid was then sucked and 
thoroughly pressed from the precipitated crystals. When the latter were 
dried at 120.degree. C. for 23 hours, 45.2 g of the magnesium salt of 
p-chlorophenoxyisobutyric acid (yield 100%) were obtained in the form of 
white crystals having a melting point of 319.degree. to 320.degree. C. 
This process results in a production of the magnesium salt of 
p-chlorophenoxyisobutyric acid in extremely high yields, which are close 
to and in some cases even as high as the theoretically possible yield. For 
this reason the process affords advantages as regards process technology 
and economy. 
EXAMPLE 8 
50 g ammonium chloride were dissolved in 140 g demineralized water with 
gentle heating. 11 g (about 0.11 mole) basic magnesium carbonate 
(light-weight powder Ph.Eur.I) were stirred into the resulting solution. 
When the resulting mixture was heated to the boil with reflux cooling for 
1 hour, ammonia gas was released and a yellowish solution was obtained, 
which was filtered. The filtrate was colorless and clear. 
42.9 (0.20 mole) p-chlorophenoxyisobutyric acid were dissolved in 60 g 
aqueous ammonia solution (10% concentration). The resulting solution was 
filtered. When the magnesium-containing solution, heated to 80.degree. C., 
was stirred into the filtrate which contained the 
p-chlorophenoxyisobutyric acid, the magnesium, salt crystallized 
immediately. The reaction mixture was cooled to room temperature and 
thoroughly stirred and the liquid was then sucked from the crystals. When 
the latter were dried at 120.degree. C. for 19 hours, 43.37 g of the 
magnesium salt of p-chlorophenoxyisobutyric acid (yield 96%) were obtained 
in the form of white crystals having a melting point of 316.degree. to 
319.degree. C. 
For instance, important advantages regarding process technology result from 
the reaction in the presence of ammonium ions and gaseous ammonia because 
the p-chlorophenoxyisobutyric acid is reacted in an ammonia solution which 
contains more ammonium ions than p-chlorophenoxyisobutyric acid.