5-methylimidazole-4-carboxylic acid ethyl

In an initial step, 2-chloroacetic acid ethyl ester is reacted with formamide to give 5-methylimidazole-4-carboxylic acid ethyl ester. Then sodium in ammonia is used to convert that to 4-hydroxymethyl-5-methylimidazole-hydrochloride. Cysteamine HCI (HSCH2CH2NH2-HCI) is then reacted to give 4-(2-aminomethyl)-thiomethyl-5-methyl-imidazole dihydrochloride. Then N-cyanamido-5,5-dimethyl-dithio-carbonate (from cyanamid, KOH, CS2 and ((CH3)2S04) is reacted to give a further intermediate which is finally reacted with methylamine to give cimetidine. 

Triphenyloxazole (5g), formamide (40g) and liquid ammonia (lOOtnl) are heated in an autoclave at 200-210°C (5h). The brownish reaction product is poured into water, and the flocculent precipitate is filtered, washed with water and recrystallized from ethanol (4.3 g, 85%), m.p. 273°C. Similarly prepared are 2,5-diethyl-4-phenyl- (25%), 2-methyl-4,5-dipropyI-(70%) [41], 4-eihyl-5-phenyl- (50%), 4-phenyl-5-propyl- (40%) and4-benzyl-5-ethyl imidazoles (5%) [40]. From 2-methyloxazole-4-carboxylic acid boiled at 150°C in a sealed tube with aqueous ammonia is obtained 2-methylimidazole (22%) boiling with aniline gives 2-methyl-l-phenylimidazole (67%) [52]. 

The oxidation of the hydroxymethyl group probably takes place more readily than nitration of the ring [124-127], However, the entry of a nitro group into the imidazole ring without oxidation of the hydroxymethyl group has been reported [107, 110]. Imidazolecarboxylic acids are not nitrated, and their nitro derivatives are therefore obtained by different methods. Nevertheless, the 4- and 5-mononitro-substituted compounds were isolated with the 4,5-dinitro derivative as impurity during the nitration of ethyl l-methylimidazole-2-carboxylate with a mixture of 100% nitric and sulfuric acids at 95°C [128],... 

For many years it was not possible to introduce two nitro groups into the imidazole ring [159], By the use of a somewhat unusual nitration condition (by heating the substrate first with nitric add and then with the sulfuric-nitric acid mixture) it was possible to obtain 4,5-dinitroimidazole [79], The method has now also been used for the production of 4,5-dinitroimidazoles [84, 93, 160], It was also shown that C-polynitrobisimidazoles [79] and not /V-nitroimidazolcs, as considered earlier [161], are formed during the nitration of 2,2 -bisimidazole and its bromine derivatives. As already mentioned earlier, during the nitration of ethyl l-methylimidazole-2-carboxylate the 4,5-dinitro derivative was also isolated together with the other nitration products [128], Increase in the reaction time increases the amount of the dinitro derivative. 

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