JPS623839B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an advantageous method for the purification of adenine. More specifically, adenine, which is the origin of arylazomalononitrile, is obtained by reacting arylazomalononitrile with formic acid or a formic acid derivative under catalytic reduction conditions in the presence of ammonia, or adenine or arylazomalononitrile, which is obtained by reacting arylazomalononitrile with formic acid or a formic acid derivative in the presence of ammonia. Purifying adenine obtained by reacting 4,6-diamino-5-arylazopyrimidine obtained by reacting with a derivative with formic acid or a formic acid derivative under catalytic reduction conditions, or adenine obtained by a similar method. The catalyst and reaction by-products are separated by adjusting the pH of the system to 7.5-9.0 and/or by adding an inorganic salt such as mirabilite or common salt, followed by decolorization in the form of an inorganic salt of adenine. The present invention relates to a method for purifying adenine characterized by the following. A common method known for purifying adenine is to boil the reactant with water and decolorize it using an adsorbent such as activated carbon. In addition, as special examples, impurities can be removed by adsorption on an activated carbon column and elution with aqueous ammonia, passing through a cation exchange resin (e.g. Amberlite 120B) column, or oxidative decomposition with potassium permanganate under acidic conditions. Methods of purification by removal and subsequent decolorization of activated carbon are known. There are also examples of purification by sublimation. A method for producing adenine using arylazomalononitrile as a starting material is, for example, a method for producing adenine in the presence of ammonia under catalytic reduction conditions of arylazomalononitrile and formamide described in Japanese Patent Publication No. 51-23516 (Patent No. 931627). can be,
Alternatively, 4,6-diamino-5
The present invention is typified by a method for producing adenine by obtaining an arylazopyrimidine and reacting it with formic acid or a derivative of formic acid under catalytic reduction conditions, and the present invention relates to the methods of these applications and reactions and reactions using reaction reagents that can be analogized thereto. It can be applied to the purification of adenine by a similar reaction such as a reaction using a reagent with a promoting effect. The purity of the crude adenine obtained by these methods is approximately 80-90%, with the remainder being the catalytic reduction catalyst and amorphous by-products. Raney nickel is commonly used as a catalytic reduction catalyst, and the amorphous by-product is a greenish-gray clay-like substance. In order to purify this crude adenine,
A general method for preparing adenine, namely, heating and refluxing crude adenine with 40 to 50 times as much water as it, dissolving the adenine, and decolorizing it with activated carbon, was investigated, but this method was inconvenient in terms of purity and whiteness. We also investigated known methods, but they were not sufficiently effective.
Both were unsatisfactory, such as a large amount of refining loss and increased costs. The inventor researched various industrially applicable purification methods, and found that by-products can be removed from hot solutions by making the pH of the solution slightly alkaline at 7.5 to 9.0, or by adding salts such as mirabilite and common salt. It was found that it precipitates as an insoluble substance. Furthermore, it was discovered that decolorization can be effectively carried out by adding mineral acids such as sulfuric acid, hydrochloric acid, and phosphoric acid to the system to lower the pH to below the point at which adenine forms salts with those acids, and then heating the system with activated carbon. Ta. By combining these two processes, it became possible to obtain adenine with extremely high purity and high whiteness. The process of purification involves recovering the reaction solvent from the reactants and adding 35 to 80 times the amount of the reaction solvent to the resulting residue, preferably 45 to 80 times as much.
Add 60 times as much water and adjust the pH to 7.5 to 9.0, preferably 7.5 to 8.5 with an alkali (preferably sodium hydroxide), and in addition or without adjusting the pH, add inorganic salts to the residue preferably 10 to 100%. 25-50%
Add mineral acid to dissolve the adenine, heat to remove insoluble matter, then add mineral acid to lower the pH to the point at which salts are formed. Add activated carbon to decolorize when heated, pass through the waste activated carbon, and pour the liquid into caustic soda. The process consists of neutralizing with an alkali such as, cooling and crystallizing. In this case, of course, crystals may be taken out after each step. Of course, PH adjustment and salt addition may be used in combination to remove by-products. The alkali used here is generally conveniently caustic soda, but there is no problem with caustic potash, soda carbonate, potassium carbonate, calcium hydroxide, etc.
Inorganic salts include mirabilite, common salt, ammonium carbonate,
Examples include ammonium phosphate, but mirabilite is the most convenient. Sulfuric acid, phosphoric acid, hydrochloric acid, etc. can be used as mineral acids. Oxidation with hydrogen peroxide, sodium hypochlorite, and potassium permanganate is a method for removing amorphous byproducts.
Reduction methods using monozinc acetate and sodium dithionite were also investigated, but their effectiveness was lower than that of the method of the present invention. In addition, the effect of ion exchange resin on decolorization was investigated, but only unsatisfactory results were obtained. The pH for forming each mineral acid salt is sulfuric acid, hydrochloric acid, and phosphoric acid, each having a pH of about 3 or less, preferably from 2.5 to 1.5. Next, the method of the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these Examples in any way. Example 1 68.1 g of phenyl azomalononitrile was dissolved in 681 g of formamide containing 6% ammonia and reacted in an autoclave at 150 to 155°C for 2 hours. Releases volatile gas when hot, then cools down to 10g of Raney Nickel
was added and a reduction reaction was carried out at 150 to 155°C for 5 hours under an initial hydrogen pressure of 80 kg/cm ² . After cooling, it was taken out from the autoclave, formamide was distilled under reduced pressure, and the precipitate was taken out and washed with methanol. crude adenine
44.2g was obtained. 10 g of the obtained crude adenine was added to 500 ml of purified water and heated, and the pH was adjusted to 8.5 by adding 48% caustic soda little by little at 80-90°. Adenine was dissolved by heating at 90-95° for 1 hour, the hot catalyst and precipitated insoluble matter were separated, and the liquid was cooled and crystallized at 10°C for 10 hours. The precipitated adenine crystals were collected by suction and washed with a small amount of purified water. The obtained crystals are purified with water.
100ml and gradually add concentrated sulfuric acid to the suspension to adjust the pH.
After adjusting the temperature to 2.0, the mixture was heated to dissolve the crystals, activated carbon was added, and heated under reflux for 1 hour to decolorize the mixture.The hot activated carbon was separated, and the precipitated crystals were collected after cooling and crystallization. Dissolve this sulfate in 500ml of purified water and pH it with caustic soda.
Adjust the temperature to 6.5 to 7, add a small amount of activated carbon, heat for 30 minutes, remove the activated carbon, cool the liquid, crystallize adenine as white crystals, suck it up, wash thoroughly with purified water, and dry. 7.5 g of adenine was obtained. The purity of this product was 99.8% as determined by ultraviolet absorption spectroscopy (UV), and 0.083% as determined by high performance liquid chromatography (HPLC) using a cation exchange column. The measured whiteness at a wavelength of 430 nm was 95.2%. Example 2 6.9 g of adenine was obtained in the same manner as in Example 1 except that hydrochloric acid was used instead of sulfuric acid. Purity 100.3% Impurities 0.096% Whiteness 95.0% Example 3 The procedure was the same as in Example 1 except that phosphoric acid (75%) was used instead of sulfuric acid and 180 ml of water was used to dissolve the phosphate. 7.8g of adenine was obtained. Purity: 99.5% Impurities: 0.033% Whiteness: 96.1% Comparative Example 1 10 g of the crude adenine from Example 1 was added to 500 ml of water and heated to reflux to dissolve the adenine, the insoluble matter was separated when heated, activated carbon was added to the liquid and heated for 1 hour. It was decolorized under reflux and the activated carbon was separated. Since the liquid had a light brown color, activated carbon was added again and decolorization was repeated, followed by crystallization. 6.5 g of adenine Purity: 95.3% Impurities: 4.2% Whiteness: 83.4% Example 4 10 g of the crude adenine from Example 1 was added to 500 g of purified water, and 3.0 g of Glauber's salt was added to the mixture and heated under reflux for 1 hour. The catalyst and insoluble matter were separated by heating, and the liquid was cooled and crystallized at 10° C. for 10 hours. The obtained adenine crystals were treated in the same manner as in Example 2 to obtain 7.5 g of adenine. Purity: 99.4% Impurities: 0.38% Whiteness: 93.7% Examples 5 to 14 10 g of crude adenine from Example 1 was prepared in the same manner as in Examples 1 and 4, with different types and amounts of salts, PH adjustment, and addition of salts. The results of the manipulations when used together are shown in Table 1.

[Table] Comparative Example 2 7.1 g of adenine was obtained in the same manner as in Example 1 except that 5 ml of hydrogen peroxide (30%) was used instead of pH adjustment. Purity 98.0% Impurities 1.5% Whiteness 92.5% Example 15 10.0 g of crude adenine from Example 1 was added to 500 ml of purified water.
The pH was adjusted to 8.0 by gradually adding 48% caustic soda at 80-90°. The adenine was dissolved by heating to 90-95° and the insoluble materials were separated. 30% sulfuric acid was gradually added to the solution to adjust the pH to 2.5.
Activated carbon was added and decolorized by heating for 1 hour, and the activated carbon was separated. 48% caustic soda was added to the solution to neutralize it to pH 7. After decolorizing the mixture by adding a small amount of activated carbon, the activated carbon was removed and the liquid was cooled to precipitate adenine crystals. The crystals were collected by suction, thoroughly washed with purified water, and dried. 8.2 g of adenine Purity: 98.9% Impurities: 0.26% Whiteness: 93.1% Example 16 8.5 g of adenine was obtained in the same manner as in Example 15, except that 4.5 g of Glauber's salt was further added. Purity 99.3% Impurities 0.12% Whiteness 93.6% Example 17 68.1 g of phenylazomalononitrile was dissolved in 681 g of formamide containing 6% ammonia, 10 g of Raney nickel was added, and the mixture was dissolved in an autoclave under an initial hydrogen pressure of 100 Kg/cm ² Reduction was carried out at 130-135° for 1.5 hours, then the temperature was raised and the reaction was carried out at 150-155° for 5 hours. After cooling, the reaction product was taken out of the autoclave and distilled under reduced pressure to recover formamide, and the residue was washed with methanol to obtain 35.1 g of crude adenine.
I got it. Example 2 10.0g of the obtained crude adenine
6.8g of adenine was obtained in the same manner as above. Purity: 100.3% Impurities: 0.13% Whiteness: 93.5% Example 18 10.0 g of the crude adenine from Example 17 was treated in the same manner as in Example 15 to obtain 7.3 g of adenine. Purity 98.8% Impurities 0.48% Whiteness 92.8%

Claims (1)

[Claims] 1. In purifying adenine produced from arylazomalononitrile, separation from reaction by-products containing catalysts is carried out by adjusting the pH of the system to 7.5 to 9.0 and/or adding inorganic salts. , followed by decolorization in the form of an inorganic salt of adenine. 2. The method for purifying adenine according to claim 1, wherein the adenine is an adenine obtained by reacting arylazomalononitrile with formic acid or a formic acid derivative under catalytic reduction conditions in the presence of ammonia. 3 Adenine is obtained by reacting arylazomalononitrile with formic acid or a formic acid derivative in the presence of ammonia, and reacting the resulting 4,6-diamino-5-phenylazopyrimidine with formic acid or a formic acid derivative under catalytic reduction conditions. A method for purifying adenine according to claim 1, which is adenine. 4. The method for purifying adenine according to claim 1, wherein the inorganic salt of adenine is a sulfate, a phosphate, or a hydrochloride. 5. The method for purifying adenine according to claim 1, wherein the added inorganic salt as an impurity separation promoter is selected from mirabilite, common salt, ammonium chloride, ammonium carbonate, and monoammonium phosphate. 6. The method for purifying adenine according to claim 1, wherein the arylazomalononitrile is phenyl azomalononitrile.