JPS5818367A - Preparation of nitrosopyrimidine derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound which is an intermediate for purine derivatives, etc., has good filterability and is easily pulverizable after the drying, by nitrosating a 4- aminopyrimidine obtained by the ring closure of a cyanoacetic acid derivative with a ring closing agent under alkaline conditions at an acidic pH of the system. CONSTITUTION:A cyanoacetic acid derivative of formulaI(X is 1-4C lower alkoxyl) is reacted with a ring closing agent expressed by formula II (Y is OH, NH2 or SH) in the presence of an alkaline catalyst to give a 4-aminopyrimidine derivative, which is directly nitrosated with a nitrite to afford a nitrosopyrimidine derivative. In the process, the pH of the system containing the 4- aminopyrimidine derivative is once adjusted from an alkaline value to an acidic one, preferably a pH<=4, particularly 1.5-2.5, and the nitrite is added to give the aimed nitrosopyrimidine derivative, having good filterability, and easily pulverizable after the drying. USE:An intermediate for pteridine.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a nitrosopyrimidine derivative which has good P11& property and is soft when dried and is easily pulverized.

/However, in the formula, Y is 01 (represents NH2 and S11)
A 4-aminopyrimidine derivative is formed by reacting with a ring-closing agent represented by generally in the presence of an alkali catalyst such as a metal alcoholade, and then nitrosation with a nitrite without isolation of the 4-aminopyrimidine derivative produced. The present invention relates to a method for producing nitrosopyrimidine derivatives, which comprises adding nitrite to a reaction liquid glue (containing a 4-aminopyrimidine derivative), which is once made alkaline and then acidic.

4-Amino-5-nitrosopyrimidine derivatives are used as intermediates in the production of purine derivatives and pteridine derivatives [
It is well known that it is an industrially important compound.

A method for producing a 4I-amino-5-nitrosopyrimidine derivative is a method in which a 4-aminopyrimidine derivative is reacted with a nitrite (for example, Org, 5ynth, Co11.
Vol4 P, 247. Ann, 381.64 (19
04)) or 8, 521 (195B)) in which a nitrosocyanoacetic acid derivative is reacted with a ring-closing agent are known.

The former of these known production methods involves isolating 4-aminopyrimidine and then nitrosating it with nitrite in acetic acid or mineral acid.

However, in actual industry, 4. When producing -amino-5-nitrone pyrimidine derivatives, a method of isolating 4-amino pyrimidine derivatives is not adopted, and 4. - The reaction system in which the aminopyrimidine derivative was formed is diluted with condensed water from which the solvent has been recovered, and nitrite is added.
Next, a method of neutralizing with acid is adopted. However, when using this method to isolate the 4-amino-5-nitrosopyrimidine derivative, the filtration properties were extremely poor, which not only took a long filtration time but also made washing with water difficult. It is extremely difficult to remove the impurities mainly composed of inorganic substances, and the present invention was completed by forming a very hard lump when dried.

The present invention will be explained in more detail. A cyanoacetic acid derivative represented by the general formula NCCH2C0X [wherein X represents a lower alkoxy group having 1 to 4 carbon atoms, an amine group, an amine group] or a logeno group] is converted into a cyanoacetic acid derivative represented by the general formula 〇2NC=NF.
The reaction to obtain a 4-amino-6-hydroxypyrimidine derivative by the reaction with a ring-closing agent represented by [wherein Y represents OH, NH2, or SH] is a well-known reaction, for example.

Org, -8ynth, Co11. Vol 4
r), 245, Ann,, 881.

64(19(14), Get, Pat, 156
,055 Industrial Chemistry Magazine 55.406 (1952),
There are U, S, P, 2.678, 204, etc. These known methods are highly alkaline, such as blemish metal alcoholade-alcohol, alkali hydroxide-water, and alkali hydroxide only, and the ring-closing reaction alcohol system proceeds almost quantitatively, so this method is mostly used industrially. This is preferable because it is adopted.

The feature of the method of the present invention is that after the ring-closing reaction, the solvent alcohol is recovered by an appropriate method, water is added to the residue to dissolve the 4I-aminopyrimidine derivative, and a mineral acid such as sulfuric acid or hydrochloric acid or an organic acid such as acetic acid is added. Voice 4 or less preferably 1.5-2
．． The goal is to lower it to 5.

During this operation, crystals precipitate between pH 10 and 11, and the crystal remains in a suspended state from beginning to end. Once the voice has been adjusted, nitrification is performed by adding an aqueous solution of nitrite, typically sodium nitrite. The reaction temperature for nitrosation does not need to be particularly limited, but is preferably 20-80''C. In particular, when the reaction is carried out at a high temperature, the generated NOx is likely to be released outside the system, and the efficiency of the sodium nitrite is reduced.

Any apparatus capable of aging the obtained nitroso compound 1rJ at room temperature for 8 to 5 hours may be used. By thoroughly washing with water to remove water-repellent weirs and other impurities, and drying after dehydration, a soft, easily pulverized lump can be obtained.

In contrast, after the ring-closing reaction, which is often carried out industrially, the alcohol is recovered and water is added to the residue to dissolve it.

Next, in the nitronization method in which sodium nitrite is added and the rice is neutralized with acid, the obtained nitroso form has very poor filterability, which not only results in poor productivity, but also makes washing with water inevitably insufficient. It becomes difficult to remove water-soluble impurities.

When the material is dried, it becomes a lump of very hard lumps, making grinding very difficult.

Next, the present invention will be specifically explained with reference to Examples.

Example 1 2,6-Diami2-5-nitroso-4-pyrimidinol.

228% Sodium Methylate 198. (49.59 g of methyl guaniacetate was added to 1 liter and heated and refluxed on a water bath for 2 hours. Excess methanol was recovered by distillation under normal pressure. 1 z of water was added to the residue of 1 + 1 bales and dissolved. 49% sulfuric acid was added little by little to this solution to make the voice 1.7. A solution prepared by dissolving 845v of sodium nitrite in 70ml of water was added dropwise to this solution while keeping the temperature at 36-40°C.After the addition was completed, 20%
The pH was adjusted to 4.5 with caustic soda, and the mixture was aged at room temperature for 8 hours, followed by suction filtration (aspirator). Filtration was completed in about 10 minutes and then washed eight times with 800 ml of water each time. After thorough dehydration, the solid matter was transferred to a tray and dried at 70°C in a tray-type hot air dryer. The dried lumps were soft and could be easily broken up by hand. Amount obtained? 2. (1 (928%). The purity of this drug 1 was determined to be 994% by comparing the absorption spectrum of a 4° x 10 -4% solution of 0.1N caustic soda at a wavelength of 820 nm with a standard product.

Comparative Example 1 Before adding 4.9% sulfuric acid, the same treatment as in Example 1 was carried out, and the resulting aqueous solution had 81% sodium nitrite crystals.翿'；t
'tka1. Yeah. 1□1kaka5uh. ~40'. □'1
1. 4.9% sulfuric acid was added little by little to the mixture. Suction filtration (aspirator) was carried out at a pH around 10. The filtration was extremely difficult, and it took about 7 hours just to separate the same phase, and a total of about 82 hours passed after washing three times with water of 800 ml each. The material taken out was sticky and sticky. Spread thinly on a tray 7
It was dried in a hot air dryer at 0°C. When dried, it was a very hard lump that could not be broken up by hand.

Acquisition amount 71. ? f (92,4·%). Purity 950%
Comparative Example 2 2,6-Diami2-5-Nitron-4-
78.5 f (94+.7%) of pyrimidinol was obtained. The purity of the main island was 850%.

Example 2 For 6-amino-5-nitroso-2,4-pyrimidinedione.

28% Sodium Meteller) 198. Or urea 8002
and 4.9.5 f of methyl cyanoacetate were added, the suspension was heated to 60°C for 41 hours, and a sodium nitrite aqueous solution (84.5 f of sodium nitrite dissolved in 70 °C of water) was added dropwise little by little. The reaction temperature was maintained at 60 to 70"C to carry out nitrosation. After completion of the dropwise addition, the mixture was cooled to room temperature 1, adjusted to 4.5 with 20% caustic soda, aged for 3 hours, and filtered with suction using a Nutsche filter (aspirator). The filtration was completed in about 10 minutes and then washed 8 times with 8001 nl of water each time. After thorough dehydration, the solid matter was transferred to a tray and dried in a hot air dryer at 70"C. The obtained mass was It was a soft material that could be easily broken down by hand. Amount obtained was 705 grams (90.8%). Purity was at wavelength 81.
The absorbance at 2 nm was 992% compared to the 1-strip equivalent product.

Comparison Example 8 The pretreatment process in which 49% sulfuric acid was added dropwise was carried out in the same manner as in Example 2, and 845f of sodium nitrite crystals were added to the resulting aqueous solution. While stirring, the reddish-purple slurry liquid was heated to 60 to 70°C-'fr and was suction-filtered (aspirator) using a Nutsche filter. Filtration was very difficult and required about 10 hours to separate the mother liquor. The water washing performed in Example 2 was canceled, and the resulting cake was spread on a tray and dried in a hot air dryer at 70°C. When dried, it was a very hard lump.

Obtained amount 72.1 f (92.4%). Purity is 83.8
%Met.

Example 8 6-amino-5-nitroso-2-mercapto-
4,-pyrimidinol (10) (28% sodium methylate) 100.09 to thiourea 88
．． 1y and then 49.52 ml of methyl cyanoacetate were added and heated under reflux for 3 hours. After the reaction was completed, excess methanol was recovered by atmospheric distillation, and 10,100 O of water was added to the residue to dissolve it. 4.9% sulfuric acid was added dropwise little by little to adjust the pH to 1.0. This solution was aged at 20-80°C. The resulting slurry was filtered with suction (aspirator) using Nuttae.

Filtration is completed in about 10 minutes, and then 8
Washed twice. Thoroughly dehydrate and spread the solid material on a tray to 70"
It was dried in a hot air dryer. The resulting mass was soft and could be easily broken down by hand. Acquired: f#r80
．． 14 (980%). The purity was 985% by comparing the absorbance at a wavelength of 8601 m with that of the standard product.

Comparative Example 4 Before dropping 49% sulfuric acid, 1 was treated in the same manner as in Example 8 (11), and sodium nitrite crystals 84,
, 5 f was added. Next, the reaction mixture was kept at 20-8°C and 49% sulfuric acid was added little by little to adjust the pH to 4.5. 8
Suction filtration (aspirator) was carried out using a time-aged Nutsche filter. Filtration was extremely difficult and required approximately 20 hours just to separate the mother liquor. The water washing performed in Example 8 was discontinued, and the resulting cake was spread on a tray and washed 711 times. Purity is 80.5%
Met.

Example 4 1,152 grams of sodium metal was dissolved in 250 grams of absolute ethanol, 5 U.8 r of guanidine hydrochloride was added in one room, and then 56.61 i' of ethyl cyanoacetate was added and heated for 2 hours. The subsequent treatment was carried out in the same manner as in Example 1, and 2,4-diamino-6-hydroxy 5-nitrone pyrimidine'&7], 8f, which has good filterability and is easy to crush after drying.
(9,], 99% was obtained. Motoichi's purity was 1002%.

Patent applicant: Kojin Co., Ltd. (12)

Claims (2)

[Claims] (1) General formula NCCH2C0X [However, X in the formula represents charcoal and SHf] Ring-closing agent and alkaline 4. -Aminopyrimidine! To form a conductor and then nitrosate the resulting 4-aminopyrimidine derivative with nitrite without isolating it, the system containing the 4-aminopyrimidine derivative is once made from alkaline to acidic and nitrite is added. A method for producing a nitrosopyrimidine derivative that has good filterability and is easy to crush after drying. (2) A method for producing a nitrosopyrimidine derivative within the Q5 claimed range (1), wherein the pH during the nitroso reaction is 41 or less.