Note: Descriptions are shown in the official language in which they were submitted.
~o7~)326
This invention is concerned with a new chemical process. More
particularly the process forming the subject of this invention is concerned
with the preparation of 2-aminoimidazoles of formula
N
Rl I
and with the salts thereof wherein R is selected from hydrogen, (Cl 4) aIkyl,
e.g. methyl~ ethyl, propyl~ isopropyl~ butyl, isobutyl or tert-butyl; (Cl 2)
alkoxy-(Cl 4) alkyl e.g. methoxDmethyl, 2-methoxy-ethyl, 3~ethoxr-propyl,
4-ethoxybutyl, 3-ethoxybutyl or 3-methoxy-2-butyl; phenyl; phenyl substituted
by 1 or 2 radical9 9elected from (Cl 2) alkyl, (Cl 2) alkoxy, chloro,
fluoro, bromo or nitro e.g. p-tolyl, p-methoxyphenyl, p-chlorophenyl, p-
fluorophenyl~ 3,4-dichlorophenyl, p-nitrophenyl or p-bromophenyl; biphenylyl;
phenyl-(Cl ) alkyl e.g. phenylmethyl, phenylethyl, phenylpropyl or 3-phenyl-
butyl; Rl may be hydrogen, (Cl 4) alkyl a9 above defi~ed or (Cl 2) alkoxy-
(Cl ) alkyl as above defined. Representative members of the 3alts are the
hydrochloride, hydrobrumide, hydroiodide, sulfate, perclorate, picrate,
styphnate~ trinitrobenzoate and the analog9.
From these salts, the corresponding free compounds of formula I
above can in turn be obtained by mean9 of conventional procedures.
The 2-aminoimidazole9 are useful intermediates for preparing 2-
nitroimidazole3 which represent a class of compounds which has been and still
i9 widely investigated both from the chemical point of view, because of the
new 9ynthetic approach (G.C. Lancini and Lazzari, Experientia, 2I, 83, 1965)
and from the pharmacological 9tandpoint, owing to their very interesting
antimicrobial propertie9, e9pecially with regard to their remarkable activity
again9t experimental infection by Trichomona9 vaginalis (G.C. Lancini et al.,
J.Med.Chem., 12, 775, 1969). Accordingly~ the present invention provides a
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new and valuable chemical process for the preparation of intermediates useful ;~
in turn for the preparation of 2-nitroimidazoles, for instance, by the
process claimed in United States Patent 3,420,842.
In United States Patent 3,450,709 a process is claimed for the
preparation of 2-aminoimidazoles of the formula ~;
R ~ H
2 N II
R -
in which R, R and R represent hydrogen or a lower alkyl, aryl or aralkyl
group, wherea~ R and R cannot represent simultaneously hydrogen. The
process starts from cyanamide and an -aminocarbonyl compound
R -CH-NH-R III
which, when Rl is hydrogen, is just an a -aminoaldehyde useful for the
process of the present invention. For the preparation of the a -aminoal-
dehyde, the United States patent uses the reduction of an a -aminoester with
sodium amalgam as described by Akabori, Berichte 66, 151, (1933), but
yields are generally low. More particularly, according to the United States
patent, on reduction of the a-aminoester the obtained a-aminoaldehyde, of
poor stability due to the presence of the amino and aldehydo group in the
same compound, is not isolated and is reacted with cyanamide in the same
solvent in which the reduction has taken place. However, even though the
condensation between the a-aminoaldehyde and cyanamide occurs satisfactor-
ily, the fact that the reduction of the a-aminoester to a-aminoaldehyde
with sodium amalgam occurs in very low yields causes the entire process
described in the above patent for preparing 2-aminoimidazoles to run with
very low overall yields as well.
We have now surprisingly found that sub~qtantially improved yields
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~0703Z6
o 2-aminoimidazoles are obtained i the ~aminoaldehydes are prepared by
catalytic hydrogenation of an d~amînonitrile of the ~ormula
C - N
R CH~NHRl IV
or an acid salt thereof in which R and Rl have the meanings indicated under
the formula I above.
In more detail, the process of our invention consists in hydrogen-
ating at a suitable temperature and low pressure the~-aminonitrile of formula ~ ;
IV in a water solution of a strong mineral acîd, using as the catalyst a metal
of the 8th group of the periodic table of elements adsorbed on a conventional ~
:' ,',
lQ carrier.
Thus this invention relates to a process for preparing an
~-aminoaldehyde o formula V ~-
CH0 V
: `'
or an acid salt or functional derivative of the carbonyl group thereof wherein:
R is selected from hydrogen, (Cl 4)alkyl, (Cl 2)alkoxy-(Cl_4)alkyl, phenyl,
CCl 2)alkylphenyl, ~Cl 2~-alkoxyphenyl, chlorophenyl, fluorophenyl, and
bromophenyl each of which may contain more than one halogen atom, nitrophenyl,
biphenylyl and phenyl-~Cl 4)-alkyl; Rl is selected from hydrogen, (Cl 4)alkyl,
and ~ 2)-alkoxy-~Cl 4~alkyl, which process comprises: catalytically
hydrogenating a molar proportion of an ~-aminonitrile of formula IV,
CN
¦ IV
R-CH-NH-Rl
or an acid salt thereof, and wherein R and Rl are as defined above, in the
p~esence of a metal of the 8th group of the Periodic Table of Elements
adsosbed on a conventional carrier as the hydrogenation catalyst, at a
temperature ranging from about 0C to about 100C, at low pressure, in an
aqueou5 solution of a st~ong mine~al acid and thereafter if desired isolating
the thus~obta~ned ~aminoaldehyde of formula V either as such or as a
functional derivative of the carbonyl groups therein.
::
~' ~ ~3~ ~ .
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:
When the theoretical amount o hydrogen is adsorbed, the catalyst if
filtered off and to the resulting solution cyanamide is added in at least one
lar proportion, but preferably in excess with respect to the starting ~-amino-
nitrile.
The resulting 2^aminoimidazole may then be isolated as described in
the above cited U.S. Patent 3,450,709, or according to procedures which will
be described below.
Yields are generally very satisfactory, ranging between 80 _ 85%
and re on the starting<-aminonitrile,
That ~-aminonitriles could be hydrogenated to yield ~-aminoaldehydes
in high yields is a completely new teaching~ P.N. Rylander, Catalytic
Hydrogenation over Platinum Metals, Acad. Press, London, 1967, pages 213 and
214, citing several Authors, reports that catalytic hydrogenation of
~-aminonitriles generally causes extensive hydrogenolysis, unless the amino
group bears an acyl substituent, and that hydrogenation in acetic anhydride
over platinum oxide gives the ~,~-diacetamido compound. Rylander further
states that low pressure reductions of unsubstituted ~-aminonitriles in
alcoholic hydrogen chloride over platinum oxide give diamines, while the same
reduction does not appear to be applicable to ~-aminonitriles in which the
amino group is substi-
~, . .
-3a-
... . . . . . . .. ... .... . .. .... . ... .. .
1(1703Z6
tuted Moreover, Rylander reports that reduction of ~-aminonitriles over
palladium sponge in alcoholhydrogen chloride using large amounts of catalyst,
keeping the solution always acid and working as rapidly as possible, still
leads to the diamines. Thus, no useful synthetic method is described for pre-
paring a-aminoaldehydes from ~-aminonitriles.
Accordingly, a further object of this inYention is to provide a new
and valuable process for preparing -aminoaldehydes starting from ~-aminonit-
riles. In particular, the invention provides a new and valuable process for
preparing a-aminoaldehydes of formula:
CHO
R-CH-NH-Rl V
starting from -aminonitriles of formula
C N
R-CH-NH-Rl IV
wherein R and Rl are defined as before.
As stated above, the hydrogenation is carried out at low pressure
using a metal of the 8th group as the catalyst.
Although practically all members of the 8th group may give useful
results, most ConYenient have been found to be palladium and, in a lesser
degree, platinum, ruthenium, rhodium, osmium and iridium, adsorbed on one of
the common carriers, such as charcoal. The hydrogenation temperature is not
critical, and is usually interdependent with the reaction time, A temperature
range between 0 and about 100 C has been found appropriate, and the total
time required for complete hydrogenation may range between 2 and 24 hours,
preferably between 8 and 15 hours.
The strong acidity necessary for the hydrogenation is imparted to
the modium by aqueous mineral acids, preferably hydrochloric acid, in a con-
centration of 10 por cent and more.
When the medium has adsorbed the theoretical amount of hydrogen, and
after the catalyst has been filtered off, the solution is ready for the adti-
., .. ,. .: .- .- . ~ ,- ,
1070326
tion of cyanamide to perform the second reaction step.
Cyanamide is usually added in excess over the amount calculated for
a 100 per cent yield of the starting a-aminonitrile, however, it is also pos-
sible to determine the concentration of the actually formed a-aminoaldehyde
or of the corresponding acid addition salt in the acidic solution in order to
have the yields of the above described reductive step: these yields are ge-
nerally higher than 90%. For this purpose, a sample of the solution (10 ml.)
is added with 25 ml. of a 7 per cent aqueous solution of hydroxylamine hydro-
chloride and 50 ml. of water and the resulting mixture is vigorously shaken
and allowed to stand for one hour. After this time, the acidity is titrated
by using an aqueous N 1 solution of sodium hydroxide and bromophenol-blue as
the indicator, or, preferably, determining potentiometrically the end point
at a pH interval of 2-3. Separately another 10 ml. sample of the mixture is
titrated in the same way, but without the addition of hydroxylamine hydro-
chloride.
Tho concentration of a-aminoaldehyde in the mixture is then calu-
lated using the following oquation:
g/100 ml. = (A-B).10. M.W.
1000
uhere A is the number of ml. of NlNaOH used for titrating the sample under
test, B is the number of ml. of NlNaOH used for the blank titration, and M.W.
is the molecular weight of the actually formed a-aminoaldehyde or of the
corrosponding acid addition salt.
Howover, if dosirod, tho a-aminoaldehyde can be isolated and charac-
torizod as a functional terivativo, for instance, as an acetal, a thioacetal,
as an atdition product with sotium bisulfite, or by transforming it into the
corrosponding hytrazone or hydrazone substitutet on the nitrogen atom of the
hydrazino moioty.
The final reaction step is carriet out, as above statet, by adding
an at loast molar proportion but preferably an excess of cyanamide to the
a-aminoaldehyde solution. To this purpose, 1 - 3 molar equivalents of cyana-
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mide, calculated over the starting -aminonitrile, are added to the solution
at about 0C, which is then adjusted to pH between about 4 and 7 by addition ;
of an alkali metal hydroxide or carbonate, and the mixture is heated at a
temperature of 50 - 100C for about 0,5 to 1.5 hours. After cooling, the
aqueous solution is brought to a p~ of about 1 by means of concentrated mine-
ral acids, preferably hydrochloric acid and is extracted ~ith an organic sol-
vent showing a limited solubility with water, such as, for instance, a (C3 6) ; `
alkanol. From this organic solution the 2-aminoimidazole of formula I is
precipitated, as a salt, either by treatment with a predetermined acid,
according to conventional procedures, or by addition of solvents such as, for
instanco, acetone, ethyl acetate or mixtures thereof, in which the 2-amino-
imidazoles salt contained in the above solution shows practically no solubi-
lity.
Alternatively, the aqueous solution can be brought to dryness in
vacuo and the obtained residue is taken up with an anhydrous (Cl 4) alkanol.
After filtering from any insoluble, the 2-aminoimidazole of formula I is
precipitated as a salt by treatment with a predeterminod acid according to
convontional mothods.
The following examples are given for better illustrating the pro-
cess of the present invention.
Example 1
2-Amino-5-(2-methoxyethyl)-1-methylimidazole hydrochloride
397 Grams (3.1 molo) of 4-methoxy-2-mothylamino-butyronitrile are
hydrogenated in 2500 ml. of an aqueous 20 per cent (w/v) solution of hydrogen
chloride, at a temperature of about 30C on 10% palladium charcoal as the
hydrogonation catalyst, for about 8 hours. After this time, 67.1 liters of
hydrogon (calculated at room temperaturo and atmospheric pressure), corres-
ponding to 95.5% of theory, and 6.08 mole of HCl, corresponding to 98% of
theory, are consumed. The reaction mixture is filtered from the catalyst
and the filtrate is adjusted to pH 4.5 by addition of sodium carbonate, then
10'703Z6
367 g. (8.73 mole) of cyanamide are added. The resulting mixture is heated
at about 60C for about 1 hour to complete reaction and, after cooling~ is
brought to pH 1 by means of concentrated hydrochloric acid and subsequently
extracted with 2200 ml. of butanol. After adding a mixture of 5000 ml. of
ethylacetate and 1500 ml. of acetone to the butanol solution, the title com-
pound precipitates and is recovered by filtration. Yield 478 g. (80.5%).
M.p. 120 - 22C tfrom butanol/ethyl acetate/acetone).
An allotropic modification melting at 58 - 60C can be obtained by
eYaporating to dryness the reaction mixture, taking up the residue with metha- ~
nol, filtering from any insoluble, and adding concentrated hydrochloric acid ~ -
to the methanol solution.
The yield of the reductive step has been calculated by the operative
proc~dure described on page 7 employing 35.6 ml of NaOH lN for titrating the
sample treated with hydroxylamine hydrochloride and 24.4 ml. for the blank
titration. The simple calculation gives a yield of about 90% over the start-
ing 4-methoxy-2-methylamino-butyronitrile.
Example 2
2-Amino-5-isopropyl-1-methylimidazole picrate
By operating as described in the previous example, 400 g. (4.04
lo) o~ 3-me~hyl-2-methylamino-butyronitrile are hydrogenated and the hydro-
genation product is reacted with 418 g. (9.96 mole) of cyanamide. The reac-
tion mixture is brought to pH 1 and extracted with butanol as in the previous
example. The title compound is precipitated from the butanol solution by
addition of a solution of 800 g. of picric acid in 8000 ml. of water at about
100C, Yield 1130 g. ~82.5%~. m.p. 211 - 14C. (from water3.
The intermediate 3-methyl-2-methylaminobutyraldehyde has been iso-
lated as the corresponding 2,4-dinitrophenylhydrazone hydrochloride which
melts at 228 - 30C (with decomposition).
Example 3
2-Amino-1,5-dimethyl-imidazole hydrochloride
By operating as described in Example 1, 185 g. (2.2 mole) of
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2-methylamino -propionitrile are hydrogenated and the hydrogenation product
is reacted with 285.5 g, (6.1 mole) of cyanamide. The reaction mixture is
brought to dryness and the residue is extracted with 3000 ml. of methanol.
Upon cooling and bubbling gaseous hydrogen chloride in the methanol solution,
the title compound precipitates, Yield 257 g. (82%) m,p. 267C (from metha-
nol).
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