JPS5935399B2 - Method for producing 4(5)-formylaminoimidazole-5(4)-carboxamide - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 4(5)-formylaminoimidazole-5(
4) A method for producing monocarboxamide (hereinafter abbreviated as compound ①).

More specifically, it relates to a method for producing compound (1) by thermally reacting 4(5)-cyano-5(4)-aminoimidazole (hereinafter abbreviated as compound I) with formic acid in the presence of an inert organic solvent. It is something. Hypoxanthine is a compound widely distributed in living organisms as a synthetic intermediate of nucleic acid bases, purines, especially as a constituent of nucleic acids, and plays an important role in the biological phenomena of living things. It is also a synthetic raw material for 5''-nucleotides that exhibits excellent taste.

Furthermore, it is also a synthetic intermediate for xanthine, caffein, theoprosine, theophylline, etc., and 4(5)-aminoimidazole-5(4)-carboxamide, which is obtained by hydrolyzing the compound with acid, is also used as a nucleobase, especially purine compounds. is a useful intermediate for Conventionally, methods for producing the compound include a method of formylating 4(5)-aminoimidazole 5(4)-carboxyamide with formic acid monoacetic anhydride;
5) - Method of heating aminoimidazole-5(4) monocarboxamide hydrochloride with formamide (Journa
lOfBlOlOgicalchemistryl85
Vol. 439, 1950), 1,3-diamino-1.
2.3 Method of reacting trioxyiminopropane with formic acid and zinc powder (JourmalOfHeterOcycle
icche Oku 1stry volume 2, page 253, 1965)
Methods such as the following are known.

However, in the former method, compound 1 is hydrolyzed and 4(5)-
This is a method in which aminoimidazole-5(4) is converted into monocarboxyamide and then formylated.
- 3-Diamino-1,2,3-trioxyiminopropane itself has the drawbacks of being unstable and having a low synthesis yield, and it is difficult to handle industrially, so it cannot be said to be a preferred method. In comparison, the method of the present invention obtains a compound by directly formylating Compound 1, and is a very rational method with short steps and simple operation. The inventors,
In order to overcome the drawbacks of the prior art as mentioned above, we have conducted various intensive studies on methods for producing compounds, and as a result, we have developed a method with relatively good yield using diaminomaleonitrile, a hydrocyanic acid tetramer that has recently become possible for large-scale mass production, as a raw material. Moreover, it has become easy to obtain.

The present inventors have completed the present invention by discovering that the compound can be easily obtained in good yield by heating and reacting formic acid in the presence of an inert organic solvent using Compound 1 as a raw material. Examples of inert organic solvents include benzene, toluene,
Xylene ethylene glycol dimethyl ether is preferably used and is industrially advantageous.

The amount of inert organic solvent used is usually 5 to 1 per 1 compound.
The amount is 20 times by weight, preferably 8 to 15 times by weight. There is no problem if it is less than 5 times the weight, but if it is too small, side reactions will be induced due to the correlation between the amount and concentration of formic acid used and the reaction temperature, which is not preferable.

The amount may be 20 times the weight or more, but using too much is not preferable because it relatively reduces the formic acid concentration and requires a long reaction time. Therefore, the amount of the inert organic solvent to be used should be determined in consideration of these various conditions so as to obtain the best yield. The amount and concentration of formic acid used is one of the conditions that plays the most important role in the method of the present invention, and the amount of formic acid used is 2 to 5 times by weight, preferably 3 to 4 times by weight relative to compound 1. Although the reaction proceeds even if the amount is less than 2 times the weight, the yield decreases as much as possible as the amount used decreases.
In addition, the amount may be 5 times or more by weight, but using a large amount is good in terms of shortening the reaction time, but on the other hand, the reaction may proceed too much, producing a large amount of side reactants or causing ring opening of compound H. Therefore, it is extremely undesirable.

Concentration is also one of the most important conditions that determines the rate of this reaction, including the inert organic solvent used, reaction temperature,
Although it varies depending on the reaction time and cannot be said to be constant, it is usually 80~
It is 90%. Although the reaction proceeds even if the concentration is 80% or less, it is extremely undesirable in that the reaction takes a long time and the yield decreases. Also, the concentration may be 90% or more, but
If the concentration is too high, the reaction will be as fast as possible and most of the reaction will be by-products, which is not preferable. Therefore, the amount and concentration of formic acid to be used should be selected so as to obtain the highest yield and be the most industrially advantageous. The reaction temperature is generally 70 to 110°C, preferably 85 to 105°C, although it is not constant because it is correlated with the amount and concentration of formic acid used and the type of inert organic solvent.

The reaction time varies depending on the concentration of formic acid used and the amount of inert organic solvent used, but is generally 1 to 10 hours, preferably 4 to 8 hours.

By appropriately combining the above conditions, the compound can be easily obtained in good yield.

As a method for purifying the present compound, the objective can be easily achieved by recrystallization from a common solvent such as water, methanol, ethanol, acetic acid, etc. The method of the present invention will be explained in more detail with reference to Examples below.

Example 1 4(5)-cyano-5(4)- in a 4-necked 50ml flask
Aminoimidazole 27, xylene 30! ! Ll was charged, and 85% formic acid 6WLI1 was slowly added dropwise at room temperature while stirring.

After refluxing at 98 to 102° C. for 5 hours using an oil bath, the mixture was cooled and the precipitate was filtered, and the precipitate was sufficiently washed with 50 ml of ice water to bring the pH of the liquid to 7. 100% of precipitated product
It was dried at ℃ for 8 hours to obtain 2.3 tons of pale green powder. Yield 8
0.7% melting point was 245-250°C. 2.0 y of this pale green powder was decolorized using 0.3 y of activated carbon in 507!11 hot water, and when the oral fluid was cooled to 0 to 5°C, flaky white crystals were precipitated. Mouth 110℃
After drying for 6 hours, 1.7f was obtained, with a recrystallization yield of 85%. The melting point was 247-248.5°C. The characteristics of the reaction product were as follows.

(1) Elemental analysis value 4(5)-Formylaminoimidazole-5(4) Carboxamide: C6H6N4O2 (2) Ultraviolet absorption spectrum (ultraviolet maximum absorption) unit; mμ (3) Infrared absorption spectrum (estimated attribution) unit, aπ-(4) Thin layer chromatography - Fixed layer: Silica gel (manufactured by Talc), developing solvent (5) The reaction product was heated and reacted in a 10% sodium carbonate solution to obtain hypoxanthine with a yield of 72%. Ta.

(6) The reaction product was heated and reacted in a methanol monohydrochloric acid solution for 15 minutes to treat the reaction solution, and 4(5) aminoimidazole 5(4) monocarboxamide hydrochloride was obtained in a yield of 40%.

Example 2 Post-treatment was carried out in the same manner as in Example 1 except that 40 ml of benzene 190% formic acid 5111 was used instead of xylene 30W11 and the reaction was carried out for 8 hours.
I got it.

The yield was 73.7% and the melting point was 245-249°C. Example 3 Compound 2.27 was obtained by carrying out the reaction and post-treatment in the same manner as in Example 1 except that 35 ml of toluene and 71 f11 of 85% formic acid were used instead of 30!11 liters of xylene.

The yield was 77.2% and the melting point was 246-248°C.

Reference Example 1 Compound 1.81 was obtained by carrying out the post-treatment in the same manner as in Example 1 except that 5 ml of 99% formic acid was used instead of 6 ml of 85% formic acid and the reaction was carried out for 2.0 hours.

Claims (1)

[Claims] 1 4(5)-formylaminoimidazole, characterized in that 4(5)-cyano-5(4)-aminoimidazole (I) is reacted with formic acid under heating in the presence of an inert solvent. -5(4) Method for producing monocarboxamide (II). ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) 2. The manufacturing method according to claim 1, wherein the inert solvent is an organic inert solvent. 3. The manufacturing method according to claim 1 or 2, wherein the concentration of formic acid is 80 to 90%. 4. Claim 1, 2 or 3, wherein the amount of formic acid used is 2 to 5 times the weight of 4(5)-cyano-5(4)-aminoimidazole (I). manufacturing method. 5. The manufacturing method according to claim 1, 2, 3, or 4, wherein the reaction temperature is 70 to 110°C.