JPS624392B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for producing adenine. More specifically, the general formula (): (In the formula, Ar represents an aryl group) The production of adenine is characterized in that a malononitrile derivative represented by the formula (Ar represents an aryl group) is heated and reacted with formic acid or a formic acid derivative in the presence of ammonia, and then the coexistence of ammonia is prevented during the catalytic reduction reaction. Regarding the law. Conventionally, methods for producing adenine using arylazomalononitrile as a starting material have been disclosed in Japanese Patent Publication No. 51-23516, Japanese Patent Application Laid-open No. 81394-1973, and Japanese Patent Application Laid-open No. 1987-8139.
Publication No. 137975 is already known. The method disclosed in Japanese Patent Publication No. 51-23516 is a method for producing adenine in a one-stage reaction by reacting arylazomalononitrile with a formic acid derivative under catalytic reduction conditions in the presence of ammonia. JP-A-49-81394
The method disclosed in Japanese Patent Publication No. 53-137975 is as follows:
First, arylazomalononitrile is heated and reacted with a formic acid derivative in the presence of ammonia, and the general formula (): Adenine is produced by a two-step reaction in which a pyrimidine intermediate represented by (wherein Ar is the same as above) is produced, and the intermediate is subsequently reacted with a formic acid derivative under catalytic reduction conditions, with or without isolation. This is the way to do it. Although these methods for producing adenine are superior to previous methods, they are not necessarily satisfactory as an industrial method for producing adenine in terms of yield, purity of the crude adenine, etc. In other words, in the one-stage production method, the operation is simple, but the yield and purity are insufficient, and in the two-stage production method, the pyrimidine intermediate having the general formula () is isolated, and then the pyrimidine intermediate is newly contacted. If the reaction is carried out under reducing conditions, the yield and purity are good, but it is difficult to take the pyrimidine intermediate having the general formula () out of the system because it is a very complicated operation, so it is difficult to adopt it industrially. . In the two-stage method in which the pyrimidine intermediate having the general formula () is reacted sequentially without being taken out of the system, the yield and purity of the adenine produced are still insufficient. However, as a result of extensive research in order to overcome the above-mentioned problems, the inventors of the present invention have conducted an operation to prevent the coexistence of ammonia as much as possible in the subsequent reaction of catalytic reduction when carrying out the two-stage method. By this method, adenine can be produced in a higher yield and purity than the conventional production method, which is almost comparable to the case where the compound of general formula () is isolated without isolation. The present invention was completed based on the discovery that the present invention can be achieved. During the catalytic reduction reaction, it is most preferable that the amount of ammonia coexisting is 0% based on the liquid component of the system, but in practice it is 2% or less and at most 5%.
The object of the present invention can be sufficiently achieved if it is below, but it is limited within the above range depending on the ammonia removal method of the present invention that is actually employed. This effect of ammonia is due to the fact that the pyrimidine intermediate having the general formula () is gradually transformed into an amorphous substance by ammonia under the reaction conditions, which directly affects the yield of the catalytic reduction reaction and the product. It not only reduces purity but also acts to interfere with catalytic reduction reactions. Therefore, in order to reduce the influence of coexisting ammonia, it is desirable to increase the catalytic reduction reaction rate and lower the reaction temperature as much as possible. That is, by increasing the hydrogen pressure and performing sufficient stirring,
The rate of the catalytic reduction reaction is increased by making the reaction system as homogeneous as possible (the pyrimidine intermediate having the general formula () is poorly soluble in solvents such as formamide), and the reaction temperature is preferably 120-120°C.
Although the temperature is 160°C, the influence of ammonia can be prevented to some extent by maintaining the temperature at 120-140°C during catalytic reduction. However, these conditions depend on the equipment and all have limitations, and these methods alone cannot achieve the high yield and high purity that are the objectives of the present invention, therefore further removal of ammonia is essential. . The method for removing ammonia does not need to be particularly limited, but any method may be used as long as it can be carried out efficiently before performing the catalytic reduction reaction. For example, the reaction to form a pyrimidine intermediate having the general formula () is generally carried out at 120 to 160°C in a closed reactor. There are several methods for removing carbon dioxide, a method for temporarily cooling and reducing the pressure, a method for bubbling nitrogen gas, etc., and a method for using these in combination. In actual industrial implementation, the method for preventing the coexistence of ammonia is preferably a combination of ammonia release during heating and bubbling of a gas such as nitrogen gas. That is, the operation of releasing gas during heating is simple, and gas bubbling is convenient because it can also be used to replace nitrogen in the reactor for catalytic reduction in the next step. The present invention will be explained in more detail. General formula ()
The first stage reaction for producing a pyrimidine intermediate having the following formula is carried out in a closed container in the presence of ammonia. As formic acid derivatives, for example, formamide, formic acid esters such as ethyl formate, orthoformic acid esters such as methyl orthoformate, formamidine salts such as formamidine acetate, etc. are used, but ease of handling, price, availability, etc. For these reasons, formamide is most preferably used. In addition, when formamide, ethyl formate, etc. are used in the reaction, a solvent is not particularly required, but as a diluent, for example, lower alcohols having 1 to 4 carbon atoms, ethers such as tetrahydrofuran and dioxane, cellosolve, butyl cellosolve, etc. There is no problem in using ethylene glycol ethers, etc. When a formamidine salt is used, it is preferable to use the alcohols and ethers mentioned above as solvents. The theoretical amount of the formic acid derivative to be used is equimolar to the arylazomalononitrile.
Actually, 2 to 50 times the molar amount is used. This is because the produced pyrimidine intermediate having the general formula () is poorly soluble, so if the diluent is used, a low molar amount is sufficient, but if it is not used, the function of the diluent is also required. be. Next, the theoretical amount of ammonia to be used is an equimolar amount to the arylazomalononitrile having the general formula (), but it is actually preferably 1.5 to 10 times the molar amount. Of course, even if more ammonia is used, a pyrimidine intermediate having the general formula () will be produced, but this is not preferred because the yield and purity will decrease. The reaction temperature is preferably 120 to 160°C, and the reaction is maintained at that temperature for 1 to 10 hours. In this way, pyrimidine intermediates with general formula () can be prepared from 90 to 97
% reaction rate. Then, ammonia remaining in the system is removed.
For example, arylazomalononitrile having the general formula () is reacted with 10 parts by weight of formamide and 6 times the mole of ammonia at 150 to 155°C for 2 to 5 hours, and then the gauge pressure is 8 to 9 Kg/cm ² There is a residual pressure of Gradually open the gas release valve on the closed container to release volatile gases. In this case, be careful as opening the valve too quickly may cause the contents to blow out. Although it is naturally preferable to operate at a higher temperature for the ammonia removal effect, it is practical and convenient to carry out the operation at the reaction temperature. This method removes most of the ammonia and, depending on the composition of the reaction system and the processing temperature, the amount of ammonia can be less than 2% based on the liquid components. In order to further improve the removal rate, an inert gas such as nitrogen gas may be introduced into the system, the pressure in the system may be gradually reduced, or an inert gas may be bubbled under reduced pressure. good. In addition to the method of removing ammonia by releasing it when hot, the container can be cooled from the outside after the reaction is completed.
When the temperature has cooled to ~50°C, remove the slight remaining internal pressure by opening the gas release valve, and then introduce an inert gas such as nitrogen gas into the system to bubble it or reduce the pressure in the system. methods will also be adopted. The gas bubbling method is not necessarily sufficient as a removal method, and should be considered as an auxiliary means to the hot release method or depressurization method. For example, when nitrogen gas is bubbled into 300 g of formamide containing 8.89% ammonia by weight using a glass tube with an inner diameter of 8 mm at a rate of 500 ml/min at 28°C for 1 hour, the amount of ammonia remaining is
It was 3.20%. Subsequently, the pyrimidine intermediate having the general formula () undergoes a second reaction under catalytic reduction conditions to form adenine without being taken out of the system. The catalytic reduction conditions referred to herein are, for example, catalytic reduction conditions using a hydrogen-reduction catalyst, a hydrogen-Raney nickel catalyst, a hydrogen-palladium catalyst, or the like. The reaction temperature is preferably 120 to 180°C, and adenine can be produced in high yield and purity by maintaining the reaction temperature at this temperature for 1 to 10 hours, preferably 3 to 7 hours. The method of carrying out the above two reactions consecutively is extremely advantageous as an industrial method for producing adenine. Further, the compound arylazomalononitrile having the general formula (), which is a raw material, can be easily obtained by azo coupling malononitrile with a diazonium salt of an aromatic amine. Aniline is commonly used as such an aromatic amine, but various other aromatic primary amines having nuclear substituents can also be used. Next, the present invention will be explained in detail with reference to Examples and Comparative Examples. The purity was measured by comparing the absorbance of a 5 x 10 ^-4 % solution of 0.1N HCl at a wavelength of 262 nm with that of a standard product. Further, impurities were measured using a high performance liquid chromatogram using a cation exchange resin column, and the impurity content was calculated from the chromatogram by a relative area comparison method. Since no suitable method for directly measuring the reaction solution was found, the amount of ammonia remaining in the reaction system was determined by measuring the following assembled sample. That is, formamide was externally cooled with ice water, and ammonia gas was blown into it to saturate it.
After using this liquid as a starting sample and subjecting it to a prescribed treatment method, the specific gravity was determined by the floating method, and a calibration curve as shown in Figure 1 was created. I asked for Table 1 shows the results of removing ammonia by the thermal release method under normal pressure and mechanical stirring.
Table 2 shows the results of ammonia removal by the reduced pressure method at 0.degree. C. and under mechanical stirring.

【table】

[Table] Here, a reference example showing the influence of ammonia on the catalytic reduction reaction is described. Reference example: 14.0 g of a pyrimidine intermediate in which the aryl group in general formula () is a phenyl group, and 112 g of formamide containing the specified amount of ammonia shown in Table 3.
In addition to this, 1.3 g of Raney nickel catalyst was added, and in an autoclave under an initial hydrogen pressure of 50 kg/ ^m2 , the temperature was 130~
Catalytic reduction was carried out at 135°C for 1 hour, then the temperature was raised and reaction was carried out at 150-155°C for 4 hours.
After cooling, excess formamide was collected under reduced pressure, 280 ml of water was added to the residue, 2 g of Glauber's salt and 0.7 g of activated carbon were added, and after heating under reflux for 1 hour, the hot insoluble matter was removed, and the liquid was cooled. Adenine was precipitated. The crystals were separated and dried to obtain adenine. The yields are shown in Table 3.

[Table] From the above results, when the pyrimidine intermediate having the general formula () is catalytically reduced, adenine can be produced in high yield when the amount of ammonia is 5% or less, preferably 2% or less based on the liquid component of the system. I know what I can do. Example 1 68.1 g of phenyl azomalononitrile was dissolved in 680 g of formamide containing 6% ammonia, and the mixture was stirred and reacted in an autoclave at 150 to 155° C. for 2 hours. After the reaction was completed, the stirring speed was reduced to immediately release ammonia gas. After the residual pressure reached 0 kg/cm ² , heating was stopped and the mixture was allowed to cool. Residual ammonia is 1
The amount was less than %. Raney Nickel 10 after cooling
g was added thereto, and catalytic reduction was carried out at 130 to 135° C. under an initial hydrogen pressure of 50 kg/cm ² . Hydrogen absorption reached 90% of the theoretical value in about 1 hour. Then raise the temperature
Heated at 150-155°C for 4 hours. After cooling, the reaction product was taken out from the autoclave, and formamide was recovered by distillation under reduced pressure. After adding 2.5 g of water to the residue and dissolving most of it by heating and refluxing, insoluble materials were removed when heated, activated carbon was added to the liquid, and the mixture was decolorized by heating for 1 hour. After separating the activated carbon, it was cooled to precipitate adenine. The crystals were collected and dried to obtain 41.2 g of adenine (yield 76.2%). The purity of the adenine obtained is
98.5%, and the impurity content was 0.76%. Comparative Example 1 An experiment was conducted under the same conditions as in Example 1 except that ammonia was not removed during heating.
33.5g was obtained (yield 62.0%). The purity of the adenine obtained was 95.0%, and the impurity content was 4.76%. Example 2 Instead of releasing and removing ammonia during heating,
An experiment was conducted under the same conditions as in Example 1, except that the pressure inside the system was gradually reduced to 30 Torr after cooling, and as a result, 41.5 g of adenine was obtained (yield: 76.8%). The amount of ammonia remaining before the catalytic reduction reaction was about 1%. The purity of the adenine obtained was 98%, and the impurity content was 1.10%. Example 3 68.1 g of phenyl azomalononitrile was dissolved in 680 g of formamide containing 3% ammonia, and the mixture was stirred and reacted in an autoclave at 140 to 145° C. for 5 hours. After the reaction was completed, the stirring speed was reduced to immediately release ammonia gas, and then nitrogen gas was bubbled to further remove ammonia. The amount of ammonia remaining was a trace amount. After cooling, add 5.0g of 5% palladium on charcoal and heat to 150~ under an initial hydrogen pressure of 20Kg/ ^cm2.
Catalytic reduction was carried out at 155°C. Hydrogen absorption is approximately 1
Absorbed 85% of the theoretical value in 15 minutes. Then, a heating reaction was carried out for 4 hours. After cooling, the reaction product was taken out from the autoclave, and formamide was recovered by distillation under reduced pressure. 2.5 g of water was added to the residue and heated to reflux. Remove the insoluble matter when heated, add activated carbon to the liquid, and add 1
Decolorization was performed by heating for a period of time. After separating the activated carbon, the mixture was cooled to precipitate adenine. The crystals were collected and dried to obtain 43.7 g of adenine (yield: 80.8%). The purity of the adenine obtained was 98.5%, and the impurity content was 0.77%. Example 4 8.5 g of phenyl azomalononitrile was dissolved in 50 g of 10% methanolic ammonia, and 74.1 g of ethyl orthoformate was added to the solution at 150-155 g in an autoclave.
The reaction was heated and stirred at ℃ for 5 hours. Air cooled to 120℃
When the mixture was cooled to a temperature of 100%, ammonia was released and removed. The residual amount of ammonia was about 1%. After cooling, add 1.5g of Raney nickel, and the initial pressure of hydrogen is 80Kg/cm ²
Below, a catalytic reduction reaction was carried out at 140 to 145°C for 5 hours. After cooling, the reaction product was taken out from the autoclave, concentrated under reduced pressure, 300 ml of water was added to the residue, and most of it was dissolved by heating under reflux.
Activated carbon was added to the liquid and the mixture was decolorized by heating for 1 hour. After separating the activated carbon, it was cooled to precipitate adenine. The crystals were collected and dried to obtain 4.7 g of adenine (yield: 69.6
%). The purity of the adenine obtained was 98.3%, and the impurity content was 1.11%. Example 5 8.5 g of phenyl azomalononitrile was added to 100 g of 5% ammoniacal ethyl cellosolve, 31.2 g of formamidine acetate was added, and the mixture was reacted in an autoclave at 130-135° C. for 5 hours. After cooling, ammonia was removed by bubbling nitrogen gas while reducing the pressure in the system. Then 5% palladium charcoal
Add 1.0g, hydrogen initial pressure 40Kg/ ^cm2 , 130~135
The reduction reaction was carried out at ℃ for 5 hours. After cooling, the reactant was taken out from the autoclave, and the reactant was transferred to Example 4.
5.1g of adenine was obtained in the same manner as above (yield:
75.6%). The purity of the adenine obtained was 98.9%, and the impurity content was 0.63%. Example 6 68.1 g of phenylazomalononitrile was dissolved in 680 g of formamide containing 6% ammonia.
Add 10g of palladium charcoal and autoclave
The reaction was heated and stirred at 150 to 155°C for 2 hours. After the reaction was completed, the stirring speed was slowed down and ammonia was immediately released and removed. Next, nitrogen gas was introduced into the system at a gauge pressure of 2
After introducing up to Kg/cm ² , nitrogen gas was released. This operation was repeated three times. The residual amount of ammonia was almost 0%. Next, hydrogen gas was introduced and catalytic reduction reaction was carried out at an initial pressure of 50 Kg/cm ² at 130 to 135°C for 1 hour, and then at 155 to 160°C for 5 hours.
The reaction product was treated as in Example 1 to obtain adenine 42.0
g (yield 77.7%). The purity of the adenine obtained was 99.3%, and the impurity content was 0.52%. Comparative Example 2 An experiment was conducted under the same conditions as in Example 6, except that 6.8 g of ammonium chloride was added to the reaction system and the ammonia removal operation was not carried out. As a result, 34.8 g of adenine was obtained (yield: 64.2%). The purity of the adenine obtained is 96.1%, and the impurity content is 3.8
It was %. From the above, it can be seen that the production method of the present invention is an excellent method for producing adenine with extremely high purity and high yield.

[Brief explanation of the drawing]

FIG. 1 is a graph of the specific gravity calibration curve of ammonia formamide at 28°C.

Claims (1)

[Claims] 1 General formula (): (In the formula, Ar represents an aryl group) is heated to react with formic acid or a formic acid derivative in the presence of ammonia, and then reacted under catalytic reduction conditions to produce adenine. A method for producing adenine characterized by preventing the coexistence of ammonia. 2. The production method according to claim 1, wherein the amount of ammonia coexisting during the catalytic reduction reaction is 0 to 5% by weight based on the liquid component of the system. 3. The production method according to claim 1, wherein the method for preventing the coexistence of ammonia is a method of releasing ammonia during heating. 4. The production method according to claim 1, wherein the method for preventing the coexistence of ammonia is a method of removing ammonia under reduced pressure. 5. The production method according to claim 1, wherein the method for preventing the coexistence of ammonia is a gas bubbling method.