5-Hydroxy-1H-imidazole-4-carboxamide (herein below, also referred to as “compound A”) is a compound which is useful as a cancer inhibitor (see, Patent Document 1, for example).
The compound A is produced, for example, from 2-aminomalonamide (see, Non-Patent Document 1 and Patent Documents 1 and 2, for example).
It is disclosed in Non-Patent Document 1 that the compound A can be obtained by reacting 2-aminomalonamide with ethyl formimidate. However, because the production method has low yield, it is not completely satisfactory.
It is disclosed in Patent Document 1 that benzene sulfonate of the compound A can be obtained by reacting benzene sulfonate of 2-aminomalonamide with trimethyl orthoformate in the presence of benzene sulfonic acid. It is also disclosed that, by neutralizing the benzene sulfonate of the compound A with sodium hydrogen carbonate, it is possible to obtain the compound A.
However, this production method has disadvantages in that benzene sulfonic acid ester having genetic toxicity is generated and trimethyl orthoformate is required in a large amount. Therefore, it is difficult to say that the production method is indeed an industrially excellent production method. Further, the compound A obtained is colored and has poor storage stability. It is disclosed in Experimental Examples 1 and 2 of the Patent Document 1 that, even though the sulfonate of the compound A and the hydrochloric acid salt of the compound A are stable, color of the compound A itself is changed to navy or blue color. It is also disclosed in Patent Document 1 that, to obtain the compound A having excellent storage stability, a trace amount of acid needs to be included in the compound A. In Example 6, the compound A containing about 2.5% of benzoic acid is described. However, there is no concrete description regarding the stability.
It is disclosed in Patent Document 2 that crude crystal of the compound A can be obtained by reacting 2-aminomalonamide with triethyl orthoformate in the presence of sulfuric acid. However, this production method has disadvantageous in that a large amount of triethyl orthoformate is required and also a large amount of activated charcoal is required. Thus, it is difficult to say that the production method is indeed an industrially favorable production method. It is also described in Patent Document 2 that, by reacting crude crystal of the compound A with an acid and neutralizing it with ammonia, the compound A can be obtained. However, there is no concrete description regarding the stability.
For formulation production of the compound A, it is known that coloration with blue color can be prevented by containing an acidic material (see, Patent Document 3, for example). It is described in Patent Document 3 that “the present compound has a property of exhibiting color either by itself or caused by oxygen, heat, or light, and in a case in which the present compound is applied as an oral agent, for example, a tendency of showing more significant coloration based on more complex reaction pathways resulting from an interaction with co-existing excipients is observed.”