JP3082006B2 - Method for producing 2-alkylthio-4,6-dihydroxypyrimidine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a 2-alkylthio-4,6-dihydroxypyrimidine or a tautomer thereof which is useful as an intermediate for agricultural chemicals and pharmaceuticals, and which has high purity and high yield while suppressing the formation of by-products. It is about how to get at a rate.

[0002]

2. Description of the Related Art Conventionally, as a method for producing 2-alkylthio-4,6-dihydroxypyrimidine, 2-mercapto-
The reaction of alkali metal salts of 4,6-dihydroxypyrimidine with methyl halide is known. This type of method has a drawback that a compound alkylated at the 5-position is by-produced, and the yield using methyl bromide is 80 to 90%.
It is. In addition, methyl bromide is a specific chemical substance and its handling is not only accompanied by many restrictions, but also requires a pressurizing device due to its low boiling point of 3.56 ° C. It was not enough as an industrial production method because it was complicated.

On the other hand, under strong basic conditions, 2-mercapto-
A method of methylating an alkali metal salt of 4,6-dihydroxypyrimidine with dimethyl sulfate in an aqueous solution or alcohol has been known for a long time.
-An alkylated compound was formed and the yield was only low. Further, an improved method for suppressing N-alkylation by adding sodium sulfite to the above method has been proposed (Japanese Patent Application Laid-Open No. 3-11068), but even in this method, the suppression of N-alkylation is still insufficient. Yield of 75
% And purity were 93.7%, which were not satisfactory.

[0004] Further, when reacting 2-mercapto-4,6-dihydroxypyrimidine with dimethyl sulfate, 2
A method has been proposed in which the reaction is performed by adjusting the pH to a weak basicity of 7.5 to 8.5 with a prescribed sodium hydroxide. (JP-A-49-126687) However, when this method was repeated by the present inventors, the purity of the target product was 55.1%,
The yield was 59.3%. (Described in Comparative Example 3)

Further, in a water solvent, 2-mercapto-4,6-
A method has been proposed in which dihydroxypyrimidine, sodium bicarbonate, and dimethyl sulfate are reacted in equimolar conditions under strongly acidic conditions. [J. Chem. Soc. , 726-34
(1947)] The above-mentioned method does not adjust the pH, and is essentially a reaction in a strongly acidic solution having a pH of about 1.3, and the yield is 70%.
% Was low. (Described in Comparative Example 2)

As described above, none of the conventional methods is sufficient as an industrial method for producing 2-alkylthio-4,6-dihydroxypyrimidine.

[0007]

SUMMARY OF THE INVENTION The present invention relates to a method for alkylating 2-mercapto-4,6-dihydroxypyrimidines with dialkylsulfuric acid. It is intended to provide a method for industrially producing -4,6-dihydroxypyrimidines.

In the present invention, 2-mercapto-
The 4,6-dihydroxypyrimidines include tautomers of the compounds and alkali metal salts thereof, and the 2-alkylthio-4,6-dihydroxypyrimidines include the tautomers. Point.

[0009]

As a result of various studies on the method of alkylating 2-mercapto-4,6-dihydroxypyrimidines with dialkylsulfuric acid, the present inventor has found that while maintaining the pH in the range of 2 to 7, By reacting, the formation of by-products was unexpectedly suppressed, 2-alkylthio-4,6-dihydroxypyrimidines were obtained in high purity and high yield, and it was confirmed that the conventional problems could be solved, and the present invention was completed. did.

That is, the present invention provides a compound represented by the general formula (1)

[0011]

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(In the formula, Z represents a hydrogen atom or an alkali metal atom.)

In the method for alkylating 2-mercapto-4,6-dihydroxypyrimidine, a tautomer thereof and / or an alkali metal salt thereof with a dialkyl sulfate, the reaction system after the addition of the dialkyl sulfate is used. To a pH of 2 to 7,
The present invention provides a method for producing 4,6-dihydroxypyrimidine.

Hereinafter, the present invention will be described in detail.

The 2-mercapto-4,6-dihydroxypyrimidine used as a raw material in the present invention can have the following tautomers, and any tautomer may be used.

[0016]

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The 2-mercapto used in the present invention
Examples of the 4,6-dihydroxypyrimidines include 2-mercapto-4,6-dihydroxypyrimidine, tautomers thereof, and alkali metal salts thereof. Examples of the alkali metal salts include sodium salts, potassium salts, and the like. . The above-mentioned 2-mercapto-4,6-dihydroxypyrimidines can be used as it is, and as for the alkali metal salts, they can be used as an aqueous solution or by isolating the alkali metal salt or generating it in the reaction system. . 2-mercapto-4,6-dihydroxypyrimidine can be easily obtained by the method described in JP-B-52-7054, and its alkali metal salts can be easily obtained by a conventional method using an alkali metal alcoholate. Can be.

Examples of the dialkyl sulfate used in the present invention include dimethyl sulfate and diethyl sulfate. The amount of the dialkyl sulfate used is 1 to 3 moles based on the used 2-mercapto-4,6-dihydroxypyrimidine. , Preferably 1 to 1.5 moles.

In the present invention, the reaction is usually carried out in an aqueous solvent system, but if the reaction of the present invention is not affected, a solvent other than water may be added to the solvent system, or the reaction may be carried out in a two-layer system. It does not limit.

In the reaction operation of the present invention, the pH may be adjusted during the addition of the dialkyl sulfuric acid. Usually, the pH is adjusted to the range of 2 to 7 by adding an alkali after the addition of the dialkyl sulfuric acid. . The alkali to be added at this time is not particularly limited, and any alkali that is usually referred to as such may be used. For example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
Examples thereof include sodium hydrogen carbonate and potassium hydrogen carbonate. As an addition method, the alkali metal salt may be added as an aqueous solution or as a solid, but in order to promote the reaction smoothly, an aqueous solution is preferable. The used amount is usually 0.01 to 2.0 times mol, preferably 0.1 to 1.5 times mol, of 2-mercapto-4,6-dihydroxypyrimidine, but the pH is 2 to 7 times. The amount is not limited to this range as long as the amount is maintained. (Note that the influence on the pH at the time of the reaction, the purity and the yield is apparent from Examples and Comparative Examples 1 to 3.)

The reaction temperature applied in the present invention is 0
The reaction may be performed at a temperature of from 70 to 70 ° C., preferably from 10 to 50 ° C., for a time period during which the raw materials disappear. The reaction time of about 5 hours is usually sufficient, but may be appropriately adjusted depending on the consumption rate of the raw materials.

After the completion of the reaction, 2-alkylthio-4,6-dihydroxypyrimidines are easily obtained by acid precipitation by adding an acid. The acid used at this time is not particularly limited, and commonly used inorganic acids and organic acids may be used.

The 2-alkylthio-4,6-dihydroxypyrimidines obtained in the present invention can take the following tautomeric forms as described above, and any tautomeric forms May be obtained.

[0024]

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[0025]

The present invention exhibits, 2-mercapto-4,6-dihydroxy-pyrimidines to a method of obtaining a 2-alkyl-thio-4,6-dihydroxy-pyrimidines are reacted with an aqueous solvent a dialkyl sulfate, a pH 2 By performing the reaction in a range of from 7 to 7, the formation of N-alkylated or 5-alkylated by-products is suppressed, and 2-alkylthio-4,6-dihydroxypyrimidines can be obtained with high purity and high yield. became.

Accordingly, the present invention relates to 2-alkylthio-4,
It is suitable as an industrial production method of 6-dihydroxypyrimidine.

[0027]

The present invention will be described more specifically with reference to the following examples.

EXAMPLE 1 83.1 g (0.5 mol) of sodium salt of 2-mercapto-4,6-dihydroxypyrimidine and 500 ml of water were placed in a 1 l reaction flask connected with a condenser, a thermometer and a stirrer.
dimethylsulfuric acid 7 while stirring at 30-35 ° C.
5.7 g (0.6 mol) was added dropwise over 1 hour at the same temperature, and a 48% aqueous sodium hydroxide solution was appropriately added dropwise to keep the pH of the reaction solution at 2 to 7. Thereafter, aging was performed at the same temperature for 2 hours. The aqueous solution of 48% sodium hydroxide used was 16.7 g.

After the reaction, a 35% hydrochloric acid aqueous solution is gradually added to adjust the pH of the reaction solution to 1 or less, and the precipitated crystals are filtered and dried.
-Methylthio-4,6-dihydroxypyrimidine79.
0 g was obtained. The yield was 99.9%. When the purity was analyzed by high performance liquid chromatography, the purity was 96.9%, and the N-methyl form and the 5-methyl form were 0.1% or less. The N-methyl form represents 1-methyl-2-methylthio-4,6-dihydroxypyrimidine, and the 5-methyl form represents 5-methyl-2-methylthio-4,6-dihydroxypyrimidine.

Example 2 7-mercapto-4,6-dihydroxypyrimidine (72.1 g, 0.5 mol) and 500 ml of water were placed in an 11-reaction flask connected to a condenser, a thermometer, and a stirrer.
41 g ( 0.5 mol) of an 8% aqueous sodium hydroxide solution was added to obtain an aqueous solution of sodium salt of 2-mercapto-4,6-dihydroxypyrimidine. Thereafter, the same operation as in Example 1 was performed to obtain 74.6 g of 2-methylthio-4,6-dihydroxypyrimidine. The yield was 94.3% and the purity was 96.9%. (Analyzed by high performance liquid chromatography)

Example 3 The procedure of Example 1 was repeated, except that a 48% aqueous potassium hydroxide solution was used as an alkali metal to be added for pH adjustment, to obtain 2-methylthio-4,6-dihydroxypyrimidine. Was. The yield was 93.8% and the purity was 94.5%. (Analyzed by high performance liquid chromatography)

Example 4 The procedure of Example 1 was repeated, except that potassium carbonate was used as an alkali metal to be added for pH adjustment.
-Methylthio-4,6-dihydroxypyrimidine was obtained. The yield was 94.9% and the purity was 94.7%. (Analyzed by high performance liquid chromatography)

Example 5 72.1 g (0.5 mol) of 2-mercapto-4,6-dihydroxypyrimidine and 500 ml of water were placed in an 11 reaction flask connected to a condenser, a thermometer and a stirrer.
It was added dropwise over a dimethyl sulfate 75.7 g 1 hour with stirring at 30 to 35 ° C.. Thereafter, a 48% aqueous sodium hydroxide solution was appropriately added dropwise at the same temperature to carry out the reaction while maintaining the pH of the reaction solution at 2 to 7, followed by aging for 2 hours. The post-treatment was carried out in the same manner as in Example 1 to obtain the desired product with a yield of 94% and a purity of 94.2% (analyzed by high performance liquid chromatography).

Comparative Example 1 As in Example 1, the sodium salt of 2-mercapto-4,6-dihydroxypyrimidine and water were added, and 64 g of sodium carbonate was added thereto. In addition, add 30 to
The reaction was carried out dropwise at 35 ° C. The reaction was carried out at pH 7.8 to
Proceed under 9.4 basic conditions. The reaction solution is 3
Addition of 5% hydrochloric acid followed by acid precipitation gave 59.8 g of 2-methylthio-4,6-dihydroxypyrimidine. The yield is 75.6.
% And purity were 65.9%.

Comparative Example 2 [J. Chem. Soc., 726-734 (1947)
Additional test of described method] 300ml 4 with condenser, thermometer and stirrer connected
8.4 g of sodium bicarbonate (0.1 g)
Mol) and 200 ml of water, and 2-mercapto-
14.4 g (0.1 mol) of 4,6-dihydroxypyrimidine was added and 12.6 g of dimethyl sulfate was added at room temperature with stirring.
g (0.1 mol) was added and the mixture was aged. The pH at the end of the reaction was 1.3. The precipitated crystals are separated by filtration, washed with water, alcohol, and ether, and dried.
10.1 g of 4,6-dihydroxypyrimidine was obtained. The yield was 70%.

Comparative Example 3 [Additional test of the method described in JP-A-49-126687] A 2N sodium hydroxide aqueous solution 1 was placed in a 300 ml 4-diameter reaction flask connected with a condenser, a thermometer and a stirrer.
93 ml and 14.4 g (0.1 mol) of 2-mercapto-4,6-dihydroxypyrimidine were added, and 12.6 g (0.1 mol) of dimethyl sulfate was added at room temperature with stirring for 15 minutes. Until the temperature rose. The reaction is
It proceeded in the pH range of 12.6 to 13.0. 3 at the same temperature
The mixture was aged for 10 minutes, boiled for about 10 minutes, decolorized with activated carbon, cooled, adjusted to pH 1 with concentrated hydrochloric acid, cooled with ice, and the precipitated crystals were filtered, washed with ice water and dried. Purity 5 5.1%
Of 2-methylthio-4,6-dihydroxypyrimidine was obtained in a crude yield of 59.3%.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 239/60 BEILSTEIN (STN) CA (STN) CAOLD (STN)

Claims (1)

(57) [Claims] 1. An aqueous solvent containing a compound represented by the general formula (1): (Wherein, Z represents a hydrogen atom or an alkali metal atom.) 2-mercapto-4,6-dihydroxypyrimidine, a tautomer thereof, and / or an alkali metal salt thereof is converted to a dialkyl sulfate In the method of alkylating with dialkyl sulfate, the reaction system after the addition of dialkyl sulfuric acid
2-alkylthio-4,6
A process for producing dihydroxypyrimidine.