Preparation of 2-alkyl-4,5-dihydroxymethylimidazoles

2-Alkyl-4,5-dihydroxymethyl-imidazoles of the formula ##STR1## where R is alkyl, are prepared by a process in which an imidazole of the formula ##STR2## is reacted with not less than 2 moles of formaldehyde in the presence of a base.

The present invention relates to a process for the preparation of 
2-alkyl-4,5-dihydroxymethylimidazoles by reacting a 2-alkylimidazole with 
formaldehyde. 
2-Alkyl-4,5-dihydroxymethylimidazoles are desirable intermediates for the 
preparation of dyes and active ingredients, and are prepared by, for 
example, reduction of the corresponding imidazolecarboxylic acids. 
Monohydroxymethylimidazoles, such as 4-methyl-5-hydroxymethylimidazole, 
which is a known intermediate for drugs, are obtained, for example, in 
accordance with European Pat. No. 4,534, by reacting 4-methylimidazole 
with formaldehyde in an alkaline medium. Furthermore, 
4,5-dihydroxymethylimidazoles which contain aryl groups in the 2-position 
have been prepared by treating the corresponding 2-arylimidazoles with 
formaldehyde. This process, described in German Laid-Open Application DOS 
No. 2,618,756, is preferably carried out in an aqueous medium at a pH of 
not less than 7. It is pointed out that the reaction of imidazoles which 
do not contain an aryl group in the 2-position with formaldehyde gives 
unstable 1-hydroxymethylimidazoles (cf. page 6, lines 8 to 13). 
We have ound that 2-alkyl-4,5-dihydroxymethylimidazoles of the formula 
##STR3## 
where R is alkyl of 1 to 17 carbon atoms which may furthermore contain 
radicals of the formula R'O--, R'.sub.2 N-- or R'S--, and R' is alkyl of 1 
to 4 carbon atoms, can be particularly advantageously prepared if an 
imidazole of the formula 
##STR4## 
where R has the above meanings, is reacted with not less than 2 moles of 
formaldehyde in the presence of a base. 
The novel process gives the 2-alkyl-4,5-dihydroxymethylimidazoles in good 
yield. This advantageous result is very surprising since, on the basis of 
the information in German Laid-Open Application DOS No. 2,618,756 
concerning the reaction characteristics of imidazoles, it was not to be 
expected that 2-alkylimidazoles could be reacted with formaldehyde under 
basic conditions to give 2-alkyl-4,5-dihydroxymethylimidazoles. 
The imidazoles of the formula II which are suitable as starting materials 
contain an alkyl radical of 1 to 17 carbon atoms, such as methyl, ethyl, 
propyl, butyl or heptadecyl, in the 2-position. The alkyl radical may 
furthermore be substituted by alkyl ether, alkyl thioether or dialkylamino 
groups in which the alkyl radicals are of, for example, 1 to 4 carbon 
atoms. Examples of 2-alkylimidazoles are 2-methylimidazole, 
2-ethylimidazole and 2-isopropylimidazole. 
Not less than 2, preferably from 2 to 3, moles of formaldehyde are reacted 
per mole of 2-alkylimidazole. The formaldehyde is used, for example, in 
the form of paraformaldehyde, trioxane or an aqueous formaldehyde 
solution, advantageously as industrial aqueous solutions having 
formaldehyde contents of from 10 to 30% by weight. Methanol, which is 
present in industrial formaldehyde solutions, does not present problems. 
In the process according to the invention, the reaction of the imidazoles 
with the formaldehyde is carried out in the presence of a base, the pH of 
the reaction mixture being not less than 7, preferably from 7 to 13. The 
reaction temperatures are from 40.degree. to 180.degree. C., and the 
reaction pressure is not critical. 
Examples of suitable bases are the hydroxides of the alkali metals or 
alkaline earth metals, such as NaOH or KOH. The bases used may furthermore 
be tertiary amines, such as triethylamine, tri-n-butylamine or 
methyldibutylamine. The base, which acts as a catalyst, is employed in 
amounts of, for example, from 0.1 to 1.0, preferably from 0.3 to 0.7, mole 
per mole of imidazole. Where alkali metal or alkaline earth metal 
hydroxides are used, the pH initially established is kept constant by 
adding further amounts of the base. 
When the reaction is complete, which takes about 20-60 hours, the 
dimethylol compounds are isolated from the reaction mixture, for example 
after distilling off the volatile components. A particular industrial 
advantage of this process is that the volatile tertiary amines can be 
reused.

The 2-alkyl-4,5-dihydroxymethylimidazoles obtainable by the process of the 
invention are useful intermediates for dyes, plastics and specialty 
chemicals. The Examples which follow illustrate the invention without 
restricting it. The compounds obtained were identified by nuclear magnetic 
resonance and elemental analysis, as stated below. 
EXAMPLE 1 
2-Methyl-4,5-dihydroxymethylimidazole 
82 g (1 mole) of 2-methylimidazole and 220 g (2.2 moles) of 30% strength by 
weight aqueous formaldehyde solution are stirred for 1 hour at 60.degree. 
C., 50.4 g (0.49 mole) of triethylamine are added to the mixture, and 
stirring is continued for 48 hours under reflux at about 78.degree. C. The 
solution is evaporated to dryness under reduced pressure at a bath 
temperature of 60.degree. C., 160 g of crude product being obtained during 
this procedure. The crude product is stirred with 128 g of methanol and 32 
g of isopropanol, for 30 minutes in each case, at 50.degree. C. and at 
10.degree. C. with cooling. The colorless solid is then filtered off, 
washed with twice 200 ml of acetone and dried for 12 minutes at 45.degree. 
C. to give 91.6 g of 2-methyl-4,5-dihydroxymethylimidazole of melting 
point 182.degree.-182.5.degree. C. This corresponds to a yield of 64.5%. 
The purity (HPLC) is 99.8%. 
Elemental analysis: 
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C H N O 
______________________________________ 
calculated 50.7 7.1 19.7 22.5% 
found 50.6 7.6 19.7 22.1% 
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Mass spectrum: M.sup.+ 142. 
.sup.1 H-NMR spectrum (solvent DDMSO; TMS as internal standard, data in 
ppm): 2.18 (s, 3p) 4.35 (s, 4p). 
EXAMPLE 2 
2-Ethyl-4,5-dihydroxymethylimidazole 
The procedure described in Example 1 is followed, except that 96 g (1 mole) 
of 2-ethylimidazole are used instead of 2-methylimidazole. The 155 g of 
crude product obtained in this procedure are stirred with 52 g of methanol 
for 30 minutes at 50.degree. C. and at 10.degree. C. with cooling. The 
mixture is filtered, the product is washed with twice 150 ml of acetone 
and dried in a drying oven, and 117.5 g of 
2-ethyl-4,5-dihydroxymethylimidazole of melting point 
173.35.degree.-174.0.degree. C. are obtained. This corresponds to a yield 
of 75.4%. The purity of this sample is 99.8% according to HPLC. 
Elemental analysis: 
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C H N O 
______________________________________ 
calculated 53.9 7.7 17.9 20.5% 
found 54.0 7.8 17.7 20.5% 
______________________________________ 
Mass spectrum: M.sup.+ 156. 
.sup.1 H-NMR spectrum (solvent DDMSO) 1.15 (t, 1p) 2.55 (q, 2p) 4.4 (s, 
4p). 
EXAMPLE 3 
2-Isopropyl-4,5-dihydroxymethylimidazole 
110 g (1 mole) of 2-isopropylimidazole and 220 g (2.2 moles) of a 30% 
strength aqueous formaldehyde solution are stirred for 1 hour at 
60.degree. C., 50.4 g (0.44 mole) of triethylamine are added to the 
mixture, and stirring is continued under reflux at about 78.degree. C. The 
product crystallizes out from the mixture. After 48 hours, the mixture is 
cooled to 5.degree. C. After 1 hour, the product is isolated by 
filtration. 136.8 g of crude product are obtained, and this is washed with 
twice 200 ml of acetone and dried in a drying oven under reduced pressure 
at 450.degree. C. to give 126.1 g of 
2-isopropyl-4,5-dihydroxymethylimidazole of melting point 
199.5.degree.-201.0.degree. C. Evaporating down the filtrate gives 107 g 
of a crude product from which a further 18.5 g of 
2-isopropyl-4,5-dihydroxymethylimidazole can be obtained by stirring with 
107 g of methanol at 50.degree. C. for 30 minutes and then cooling at 
5.degree. C. for 30 minutes, filtering and drying. The total yield is 
84.8%. 
Elemental analysis: 
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C H N O 
______________________________________ 
calculated 56.5 8.2 16.5 18.8% 
found 56.7 8.6 16.5 18.2% 
______________________________________ 
Mass spectrum: M.sup.+ 170. 
.sup.1 H-NMR spectrum (solvent DDMSO): 1.12 1.24 (d, 6p) 2.9 (septet, 1p) 
4.35 (s, 4p). 
EXAMPLE 4 
2-Ethyl-4,5-dihydroxymethylimidazole 
The procedure described in Example 2 is followed, except that 90.7 g (0.49 
mole) of tri-n-butylamine are used instead of triethylamine. After 46 
hours, 10 g of formaldehyde (in the form of a 30% strength aqueous 
solution) are added and, after a total of 62 hours at 110.degree. C., the 
upper phase is separated off and the product is isolated by evaporation. 
The working-up procedure described in Example 2 gives 139.2 g of 
2-ethyl-4,5-dihydroxymethylimidazole of melting point 
173.degree.-174.degree. C. (yield 89.1%). 
EXAMPLE 5 
2-Methyl-4,5-dihydroxymethylimidazole 
41 g of 2-methylimidazole are dissolved in 20 ml of water, 100 g of a 30% 
strength aqueous formaldehyde solution are added slowly to the solution at 
from 15.degree. to 25.degree. C., and the pH is brought to 12.4 with 9 ml 
of a 40% strength aqueous potassium hydroxide solution. The pH is kept at 
12.4 during the reaction by adding a solution of potassium hydroxide and 
aqueous formaldehyde (molar ratio 1:2). After 28 hours, the mixture is 
evaporated down and the crude product is treated as described in Example 
1. 55.7 g (yield 78.4%) of 2-methyl-4,5-dihydroxymethylimidazole of 
melting point 182.degree.-182.5.degree. C. are obtained. 
The procedure described in the first paragraph is followed, except that 8 
ml of a 40% strength sodium hydroxide solution are added instead of the 
potassium hydroxide solution, the pH thus being brought to 12.1. After 28 
hours, the mixture is evaporated down, and the residue is worked up as 
described in Example 1. 50 g (yield 70.2%) of 
2-methyl-4,5-dihydroxymethylimidazole of melting point 
182.degree.-182.5.degree. C. are obtained.