Process for the production of 2-substituted 5-chloroimidazole-4-carbaldehydes

A process for the preparation of 2-substituted 5-chloroimidazole-4-carbaldehydes of the general formula: ##STR1## in which glycine is reacted with an imido ester of the general formula: ##STR2## and the resultant intermediate is converted into the product by a Vilsmeier reagent. The 2-substituted 5-chloroimidazole-4-carbaldehydes are valuable intermediates for the preparation of pharmaceuticals or herbicidally active compounds.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The invention relates to a process for the preparation of 2-substituted 
5-chloroimidazole-4-carbaldehydes of the general formula: 
##STR3## 
in which R denotes hydrogen, an alkyl group, an alkenyl group, a 
cycloalkyl group, an arylalkyl group or an aryl group. 
2. Prior Art 
It is known in accordance with European Published Patent Application No. A 
0,614,892 to cyclize a glycine ester hydrohalide with an imido ester to 
give a 3,5-dihydroimidazole and then to convert it to the target product 
using phosphorus oxychloride in the presence of N,N-dimethylformamide. 
This process has the disadvantage that the glycine methyl ester must be 
liberated in each case in situ from the corresponding halide. Furthermore, 
the glycine ester hydrohalide is a relatively expensive starting material. 
The main object of the invention is to provide an economic process which 
takes the above-noted prior art disadvantages into account and which is 
able to comply with the requirements of an industrial process on a large 
scale. Other objects and advantages of the invention are set out herein or 
are obvious herefrom to one skilled in the art. 
The objects and advantages of the invention are achieved by the process of 
the invention. 
The invention involves a process for the preparation of 2-substituted 
5-chloroimidazole-4-carbaldehydes of the general formula: 
##STR4## 
in which R denotes hydrogen, an alkyl group, an alkenyl group, a 
cycloalkyl group, an arylalkyl group or an aryl group. In the first stage 
of the process, glycine is reacted with an imido ester of the general 
formula: 
##STR5## 
in which R has the meaning mentioned and R.sub.1 denotes an alkyl group, 
to give a compound of the general formula: 
##STR6## 
in which R has the meaning mentioned. In the second stage, this compound 
is converted to the end product by a Vilsmeier reagent, which is composed 
of a chlorinating agent and a formamide of the general formula: 
##STR7## 
in which R.sub.2 and R.sub.3 are identical or different and denote a 
(C.sub.1 -C.sub.4)-alkyl group or an aryl group. 
Preferably the compound of the general formula III is not isolated before 
the second stage. Preferably the reaction in the first stage is carried 
out at a pH between 4 and 12 and at a temperature between -20.degree. C. 
and 80.degree. C. Preferably the chlorinating agent used in the Vilsmeier 
reagent is phosphorus oxychloride. Preferably the formamide of the general 
formula IV used in the Vilsmeier reagent is N,N-dimethylformamide. 
Preferably the molar ratio of chlorinating agent to formamide of the 
general formula IV in the Vilsmeier reagent is between 1 to 1 and 4 to 1. 
Preferably the reaction with the Vilsmeier reagent proceeds at a 
temperature between 60.degree. C. and 200.degree. C. 
The 2-substituted 5-chloroimidazole-4-carbaldehydes of the general formula 
I are important intermediates for the preparation of hypotensive 
pharmaceuticals (U.S. Pat. No. 4,355,040) or herbicidally active compounds 
(German Patent No. A 2,804,435). 
DETAILED DESCRIPTION OF THE INVENTION 
In formulae, I, II, III and IV, the general substituents R, R.sub.1, 
R.sub.2 and R.sub.3 have the following meanings: 
An alkyl group is taken to mean a straight-chain or branched (C.sub.1 
-C.sub.6)-alkyl group, in particular methyl, ethyl, n-propyl, isopropyl, 
n-butyl, isobutyl, t-butyl, pentyl and its isomers, or hexyl and its 
isomers. A preferred alkyl group for R is the n-butyl group. A preferred 
alkyl group for R.sub.1 is a (C.sub.1 -C.sub.4)-alkyl group, particularly 
preferably methyl. 
An alkenyl group is taken to mean a straight-chain or branched (C.sub.1 
-C.sub.6)-alkenyl group, in particular 1-propenyl, 2-propenyl, 1-butenyl, 
2-butenyl, 3-butenyl, pentenyl and its isomers, or hexenyl and its 
isomers. A preferred alkenyl group is 2-butenyl or 3-butenyl. 
Cycloalkyl is expediently taken to mean cyclopropyl, cyclobutyl, 
cyclopentyl or cyclohexyl. 
An arylalkyl group expediently has the meaning phenyl-(C.sub.1 
-C.sub.6)-alkyl, preferably benzyl. Aryl correspondingly has the preferred 
meaning of phenyl. 
The aryl group can have one or more substituents, such as, alkyl, halo, 
nitro or amino, on its aromatic nucleus. 
The term halogen expediently includes chlorine, bromine or iodine, 
preferably chlorine. 
In the first step of the process according to the invention, glycine is 
reacted with an imido ester of the general formula: 
##STR8## 
in which R has the meaning mentioned above and R.sub.1 denotes an alkyl 
group, to give a compound of the general formula: 
##STR9## 
in which R has the meaning mentioned above. 
Expediently, the reaction is performed in the first stage at a pH between 4 
and 12, preferably at 5 to 9, and at a temperature generally between 
-20.degree. C. and 80.degree. C., preferably between 0.degree. C. and 
30.degree. C. 
The glycine is customarily present suspended in a suitable solvent, such as 
an aliphatic alcohol such as methanol or ethanol, optionally mixed with 
water. The imido ester can be added in the form of a solution in an inert 
solvent, such as toluene, chlorobenzene, or an aliphatic alcohol. The 
reaction partners in the first stage are expediently used 
stoichiometrically. 
After a reaction time expediently of 2 hours to 48 hours, the resulting 
compound of the general formula III can be isolated from the reaction 
mixture in a manner known to those skilled in the art, but preferably it 
is not isolated and instead is further reacted directly to give the end 
product. 
In the second and last stage, the compound of the general formula III is 
converted into the end product by so-called Vilsmeier reagent. 
The Vilsmeier reagent is expediently composed of a chlorinating agent and a 
formamide of the general formula: 
##STR10## 
in which R.sub.2 and R.sub.3 are identical or different and denote a 
(C.sub.1 -C.sub.4)-alkyl group or an aryl group. A preferred formamide is 
N,N-dimethylformamide. 
The chlorinating agent used expediently is phosphorus oxychloride, thionyl 
chloride, phosgene or phosgene-releasing compounds, phosphorus trichloride 
or phosphorus pentachloride. A preferred chlorinating agent is phosphorus 
oxychloride. 
Expediently the molar ratio of chlorinating agent to formamide of the 
general formula IV in the Vilsmeier reagent is between 1 to 1 and 4 to 1. 
The Vilsmeier reagent is expediently used in excess, serving at the same 
time as a solvent. However, it is also possible to add an inert solvent 
such as toluene, chlorobenzene or xylene. 
The reaction temperature for the reaction in the second stage expediently 
is between 60.degree. C. and 200.degree. C. 
In the course of this reaction, an N,N-substituted aminomethyleneimidazole 
of the general formula: 
##STR11## 
in which R, R.sub.2 and R.sub.3 have the meaning mentioned, is formed as 
an intermediate. 
This intermediate is the subject-matter of the European Published Patent 
Application No. A 0,653,422. 
After a reaction time of generally 1 hour to 24 hours, the corresponding 
2-substituted 5-chloroimidazole-4-carbaldehyde can be obtained in good 
yield and purity in a manner known to those skilled in the art, 
expediently by treating the reaction mixture with water and extraction 
with a suitable solvent.

EXAMPLE 1 
Preparation of (Pentanimidoylamino)acetic Acid 
A stirred suspension of glycine (18.77 g, 0.25 mol) in methanol (80 ml) and 
water (4.5 ml) was cooled to 0.degree. C. and adjusted to pH 9.6 by adding 
30 percent strength sodium hydroxide solution. Methyl pentanimidate (68.81 
g of a 42 percent strength solution in toluene=0.25 mol) was added to this 
suspension over the course of 5 minutes. After stirring for 18 hours at 
room temperature, the suspension was filtered, and the filter cake was 
washed with toluene (75 ml) and dried. The yield of the title compound was 
25.45 g (purity&gt;95 percent by H-NMR), 64 percent based on glycine. Other 
data concerning the title compound was: 
.sup.1 H-NMR (CH.sub.3 OD, 400 MHz) .delta. 0.94 (3H, t); 1.43 (2H, m); 
1.70 (2H, m); 2.50 (2H, t); 3.75 (2H, s). 
EXAMPLE 2 
Preparation of (Pentanimidoylamino)acetic Acid 
A stirred suspension of glycine (18.77 g, 0.25 mol) in methanol (80 ml) and 
water (4.5 ml) was cooled to 0.degree. C. and adjusted to pH 9.6 by adding 
30 percent strength sodium hydroxide solution. Methyl pentanimidate (67.12 
g of a 42.9 percent strength solution in toluene=0.25 mol) was added to 
this suspension over the course of 7 minutes. The reaction mixture was 
stirred for 5 hours at room temperature. Methanol and water were then 
distilled off at a reduced pressure of 30 mbar to 150 mbar. In total, 250 
ml of toluene was added during this distillation. The mixture was then 
filtered, and the filter cake washed with toluene (75 ml) and dried. The 
yield of the title compound was 39.61 g (purity approximately 90 percent 
by H-NMR), 90 percent based on glycine. 
EXAMPLE 3 
Preparation of 2-Butyl-5-chloroimidazole-4-carbaldehyde 
Phosphorus oxychloride (43.80 g, mmol) was added to a suspension of 
(pentanimidoylamino)acetic acid (15.82 g, 100 mmol) in toluene (75 ml) in 
the course of 5 minutes. The mixture was heated to 80.degree. C. and then 
admixed with N,N-dimethylformamide (20.57 g, 280 mmol) in the course of 7 
minutes. The temperature rose in the course of this to 96.degree. C. After 
stirring for 2 hours at 100.degree. C., the mixture was cooled to 
30.degree. C. The reaction mixture was then poured with stirring into 80 
ml of water in such a manner that the temperature could always be kept 
below 30.degree. C. After addition of ethyl acetate (80 ml) and Celite (5 
g), the pH of the mixture was adjusted to 1.2 with 30 percent strength 
sodium hydroxide solution. The mixture was filtered, then phase separation 
took place at 30.degree. C. The organic phase was washed twice with water 
and then concentrated to dryness. The title product was obtained in a 
yield of 13.39 g (HPLC purity 81.4 percent), 50 percent based on 
(pentanimidoylamino)acetic acid. 
EXAMPLE 4 
Preparation of 2-Butyl-5-chloroimidazole-4-carbaldehyde Without Isolation 
of (Pentanimidoylamino)acetic Acid! 
A white suspension of 37.91 g (0.50 mol) of glycine, 9.0 g (0.50 mol) of 
water and 160 ml of methanol was cooled to 0.degree. C. The pH was 
adjusted to 9.5 by addition of 30 percent strength sodium hydroxide 
solution. 140.46 g of a solution of methyl pentanimidate (41 percent 
strength=0.50 mol) in toluene was added dropwise in the course of 11 
minutes, so that the temperature could be kept at 0.degree. C. The 
reaction mixture was stirred for 20 hours at room temperature, after which 
the pH was adjusted from 10.13 to 7.0 by the addition of concentrated 
sulfuric acid. 500 ml of toluene was added and methanol and water were 
distilled off under vacuum. After the distillation, 72.6 g of toluene was 
added. The weakly yellowish suspension was cooled to 0.degree. C. and 
219.0 g (1.40 mol) of phosphorus oxychloride was added in the course of 11 
minutes. After 20 minutes, the mixture was heated to 80.degree. C., 102.9 
g (1.40 mol) of dimethylformamide was added, the mixture was heated for 2 
hours at 100.degree. C., allowed to cool to 35.degree. C. and, with 
stirring, poured into 350 ml of water so that the temperature could be 
kept below 30.degree. C. The mixture was admixed with 300 ml of ethyl 
acetate and 20 g of Celite, and stirred for 15 minutes at 25.degree. to 
30.degree. C. The pH was adjusted to 1.20 by the addition of 2.75 ml of 30 
percent strength sodium hydroxide solution. The Celite was filtered off 
with suction at approximately 30.degree. C. and the phases were separated 
at approximately 30.degree. C. The organic phase was washed twice with 
water and concentrated to dryness. The yield of the title compound was 
68.1 g (HPLC purity 85.0 percent), 62 percent based on glycine. 
EXAMPLE 5 
Preparation of (Benzimidoylamino)acetic Acid 
A white suspension of glycine (3.81 g, 50 mmol) in water (0.9 g) and 
methanol (16 ml) was stirred at room temperature, adjusted to pH 9.6 by 
the addition of sodium hydroxide solution and admixed with ethyl 
benzimidate (7.69 g, 50 mmol). The mixture was heated for 1 hour at 
50.degree. C. and allowed to cool at room temperature. The solid was 
filtered off, washed with toluene and dried at room temperature/30 mbar. 
The yield of the title compound was 6.81 g (approximately 95 percent pure 
by H-NMR), 74 percent based on glycine. Other data concerning the title 
compound was: 
.sup.1 H-NMR (D.sub.2 O, 400 MHz) .delta. 4.09 (2H, s); 7.63 (2H, m); 7.76 
(3H, m). 
EXAMPLE 6 
Preparation of 5-Chloro-2-phenyl-3H-imidazole-4-carbaldehyde 
A suspension of (benzimidoylamino)acetic acid (4.38 g, 25 mmol) in toluene 
(25 ml) at 0.degree. C. was admixed over the course of 5 minutes with 
phosphorus oxychloride (10.73 g, 70 mmol). After addition of toluene (19 
ml) the mixture was heated to 80.degree. C., admixed with 
N,N-dimethylformamide (5.12 g, 70 mmol) and reacted further for 2 hours at 
100.degree. C. The reaction mixture was poured into water (19 ml) so that 
the temperature could be kept below 30.degree. C., and the reaction flask 
was rinsed with ethyl acetate (15 ml). The reaction mixture was admixed 
with Celite (2.25 g), stirred for 0.5 hours at 25.degree. C., and adjusted 
to pH 1.2 by the addition of 30 percent strength sodium hydroxide solution 
(7.3 ml). The mixture was filtered and the phases were separated. The 
organic phase was washed twice with water and concentrated to dryness. The 
yield of the title compound was 4.13 g (approximately 95 percent pure by 
H-NMR), 76 percent based on (benzimidoylamino)acetic acid. Other data 
concerning the title compound was: 
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta. 7.5 (3H, m); 8.1 (2H, m); 9.77 
(1H, s); 11.7 (1H, br. s).