JPH08198858A - Production of 5-chloro-4-hydroxy-6-methylpyrimidine - Google Patents

Abstract

PURPOSE: To obtain new 5-chloro-4-hydroxy-6-methylpyrimidine by suppressing decomposition of a formamidine salt and using a liquid raw material easily handleable industrially in a reaction between a chlorooxobutanoic acid ester and the formamidine salt. CONSTITUTION: This method for producing 5-chloro-4-hydroxy-6-methylpyrimidine is to react (A) a formamidine salt with (B) a 2-chloro-3-oxobutanoic acid ester of the formula (R is an alkyl, preferably a 1-4C alkyl) in the presence of (C) a base (preferably sodium methylate, sodium ethylate, etc.) by simultaneously adding the component C and the component B with keeping the molar ratio in use and obtain (D) 5-chloro-4-hydroxy-6-methylpyridine. It is preferable to react 1.5-3 moles of the component A with 1 mole of the component B while 1 mole of the component C with one mole of the component B. The simultaneous addition speed of the component B and the component C is preferable to keep the reaction temperature in the range of 0-10 deg.C.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to 4,5-dichloro-methylpyrimidine (compounds described in JP-A-2-223564, JP-A-3-163066, etc.) which is useful as a raw material for producing pharmaceuticals and agricultural chemicals. The present invention relates to a novel method for producing 5-chloro-4-hydroxy-6-methylpyrimidine used as a raw material.

[0002]

Description of the Prior Art 5-Chloro-4-hydroxy-6-
The method for producing methylpyrimidine is as follows:
However, none of these methods is satisfactory as an industrial production method. SUMMARY OF THE INVENTION 5-chloro-3-oxopentanoic acid esters are reacted with a formamidine salt in the presence of a base to give 5-chloro-
A method for obtaining 6-ethyl-4-hydroxypyrimidine. According to this method, the yield of 5-chloro-4-hydroxy-6-methylpyrimidine is 81% or less, which is unsatisfactory as an industrial synthetic method.

European Patent No. 153,746: 2-chloro-3-oxobutanoic acid esters are reacted with p-methoxybenzamidine to give 5-chloro-6-
Method for obtaining methyl-4-hydroxypyrimidine. In this method, expensive p-methoxybenzamidine must be used in order to obtain the target compound, and therefore it is not satisfactory as an industrial synthetic method.

JP-A-58-220070 A method of chlorinating 4-hydroxy-6-alkylpyrimidine. In this method, it is difficult to remove the by-product produced by chlorination after the reaction of 3-oxobutanoic acid esters with the formamidine salt, and therefore it is not satisfactory as an industrial synthetic method.

[0005]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a novel 5-chloro-4-hydroxy-6-methylpyrimidine used as a raw material of 4,5-dichloro-methylpyrimidine which is useful as a raw material for producing pharmaceuticals and agricultural chemicals. To provide a simple manufacturing method.

[0006]

Means for Solving the Problems As a result of research for solving the above-mentioned problems, the present inventors have found that in the reaction of 2-chloro-3-oxobutanoic acid esters with formamidine salt, formamidine salt The inventors have found that 5-chloro-4-hydroxy-6-methylpyrimidine can be produced in high yield by using a liquid raw material that suppresses decomposition and is easy to handle industrially, and has completed the present invention.

That is, the present invention is as follows. Formula (1):

[0008]

Embedded image

2-chloro-3-oxobutanoic acid ester represented by the formula (wherein R represents an alkyl group) and a formamidine salt are reacted in the presence of a base to give 5-chloro-
In the method for producing 4-hydroxy-6-methylpyrimidine, the method is characterized in that the base and the 2-chloro-3-oxobutanoic acid ester are simultaneously added to the solvent of the formamidine salt while maintaining the ratio of the number of moles used. The present invention relates to a method for producing 5-chloro-4-hydroxy-6-methylpyrimidine. Hereinafter, the present invention will be described in detail. Examples of the base include alkali metal lower alkoxides, and preferred are sodium methylate and sodium ethylate. Examples of 2-chloro-3-oxobutanoic acid esters include R in the above formula (1).
Is preferably an alkyl group having 1 to 4 carbon atoms (eg, methyl 2-chloro-3-oxobutanoate, 2
-Ethyl chloro-3-oxobutanoate, etc.), which can be obtained and used as a commercial product.

The reaction concentration range of 2-chloro-3-oxobutanoic acid esters is 1% to 50% by weight / volume, preferably 5% to 30%. As the formamidine salt, for example, formamidine hydrochloride, formamidine acetate and the like can be used as commercially available products. Examples of the solvent include ether solvents (eg, tetrahydrofuran, dioxane, etc.), alcohol solvents (eg, methanol, ethanol, etc.), but preferably ester side of 2-chloro-3-oxobutanoic acid esters. The same type of alcohol solvent is used. The molar ratio of each component of the reaction is 1 to 5 mol, preferably 1.5 to 3 mol, of formamidine salt to 1 mol of 2-chloro-3-oxobutanoic acid ester; the base is the formamidine salt. It is preferable to use equimolar amounts. The reaction temperature is under cooling because it generates heat during the reaction, but is preferably -20 to 30 ° C, more preferably 0 to 10 ° C. The reaction time varies greatly depending on the amount of reagents to be reacted and the reaction temperature, but is usually 0.5 to
10 hours.

When the base and the 2-chloro-3-oxobutanoic acid ester are simultaneously added to the solvent of the formamidine salt while maintaining the molar ratio of the base and the 2-chloro-3-oxobutanoic acid ester to be used, the base and the 2-chloro-3-oxobutanoic acid ester are added.
The two compounds are gradually added to the solvent of the formamidine salt while maintaining the ratio of the number of moles of the chloro-3-oxobutanoic acid ester used; the addition rate is such that the reaction temperature is above the above temperature range. It is preferable to carry out at such a rate that it does not occur, more preferably 10 to 10 ° C in the temperature range.
It is preferable that the time is from 2 minutes to 2 hours. After the reaction is completed, 5-
Chloro-4-hydroxy-6-methylpyrimidine is obtained as a basic salt and is neutralized with an acid. Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid. The amount of acid used is preferably equimolar to the amount of base used. After such post-treatment, the filtrate obtained by filtration is concentrated to obtain the desired product, 5-chloro-4-hydroxy-6-methylpyrimidine. Furthermore, a high-purity product can be obtained by subjecting the obtained target product to purification treatment such as recrystallization, if necessary.

[0012]

EXAMPLES The present invention will be described below with reference to Examples and Comparative Examples. It should be noted that these examples do not limit the scope of the present invention. Example 1 Formamidine acetate (20.82 g, 0.2 mol) and methanol (125 ml) were cooled to 4 ° C.
Methyl chloroacetoacetate (15.06 g, 0.1 mol) and 28% sodium methylate in methanol (38.59 g, 0.2 mol) using a metering pump.
The mixture was added dropwise over 30 minutes at a dropping rate of 1: 2 and then stirred at room temperature (24 ° C.) for 3 hours. After completion of the reaction, 9
6% sulfuric acid (10.72 g) and water (9.5 ml) at 4 ° C
The mixture was added to the mixture while cooling to neutralize, and then refluxed at 64 ° C. for 1 hour. After the inorganic salt was filtered off by hot filtration, the filtrate was quantified to give the desired product, 5-chloro-4-hydroxy-6-
It was found that 13.66 g (yield 94.5%) of methylpyrimidine was obtained. Concentrated hydrochloric acid (8.3
(ml) and stirred for 30 minutes and concentrated under reduced pressure. Toluene (100 ml) was added and concentrated to the obtained residue, hexane (200 ml) was added, and the mixture was stirred at room temperature (24 ° C.) for 1 hour and then filtered. 13.5 by setting the target solid
g was obtained.

Example 2 Formamidine acetate (20.82 g, 0.2 mol) and methanol (125 ml) were cooled to 4 ° C.
Ethyl chloroacetoacetate (16.46 g, 0.1 mol) and 28% sodium methylate in methanol (38.59 g, 0.2 mol) were used with a metering pump.
The mixture was added dropwise over 30 minutes at a dropping rate of 1: 2 and then stirred at room temperature (24 ° C.) for 3 hours. 3 after reaction
5% Hydrochloric acid (17.11 g) was added while cooling to 4 ° C to neutralize, and then refluxed at 64 ° C for 1 hour. After the inorganic salt was filtered off by hot filtration, the filtrate was quantified to
1-chloro-4-hydroxy-6-methylpyrimidine
It was found that 3.47 g (yield 93.2%) was obtained. The obtained filtrate was concentrated under reduced pressure, and the resulting residue was mixed with water (1
0 ml) was added and dissolved by heating, and finally, while gradually cooling, with ice cooling, stirring, filtering and drying, 13.2 g of a target solid was obtained.

Example 3 Formamidine hydrochloride (16.11 g, 0.2 mol) and methanol (125 ml) were cooled to 4 ° C.
Methyl chloroacetoacetate (15.06 g, 0.1 mol) and 28% sodium methylate in methanol (38.59 g, 0.2 mol) using a metering pump.
The mixture was added dropwise over 30 minutes at a dropping rate of 1: 2 and then stirred at room temperature (24 ° C.) for 3 hours. After completion of the reaction, 9
6% sulfuric acid (10.72 g) and water (9.5 ml) at 4 ° C
The mixture was added to the mixture while cooling to neutralize, and then refluxed at 64 ° C. for 1 hour. After the inorganic salt was filtered off by hot filtration, the filtrate was quantified to give the desired product, 5-chloro-4-hydroxy-6-
It was found that 13.24 g (yield 91.6%) of methylpyrimidine was obtained.

Comparative Example 1 Formamidine acetate (31.23 g, 0.3 mol) and methanol (125 ml) were cooled to 4 ° C.
8% sodium methylate in methanol (57.8
8 g, 0.3 mol) was added dropwise, then methyl 2-chloroacetoacetate (15.06 g, 0.1 mol) was added dropwise over 50 minutes, and the mixture was stirred at room temperature (24 ° C.) for 3 hours. After the reaction was completed, 96% sulfuric acid (10.72 g) and water (9.5 ml)
Is added to the mixture while cooling to 4 ° C to neutralize, and then 1 at 64 ° C.
Reflux for hours. The inorganic salt was filtered off by hot filtration, and the filtrate was quantified to give 11.27 g of the desired product, 5-chloro-4-hydroxy-6-methylpyrimidine (yield 78.0).
%) It turned out that it was obtained.

Comparative Example 2 Methyl 2-chloroacetoacetate (15.06 g, 0.1 mol), methanol (125 ml) and formamidine acetate (20.82 g, 0.2 mol) were cooled to 4 ° C. 28% sodium methylate in methanol (3
(8.59 g, 0.2 mol) was added dropwise over 60 minutes, and the mixture was stirred at 4 ° C. for 3 hours. After completion of the reaction, 96% sulfuric acid (10.72)
g) and water (9.5 ml) were added while cooling to 4 ° C to neutralize, and then refluxed at 64 ° C for 1 hour. After the inorganic salt was filtered off by hot filtration, the filtrate was quantified to
1-chloro-4-hydroxy-6-methylpyrimidine
It was found that 1.57 g (yield 80.0%) was obtained.

[0017]

INDUSTRIAL APPLICABILITY According to the present invention, a liquid raw material which suppresses decomposition of formamidine salt and is industrially easy to handle in the reaction of 2-chloro-3-oxobutanoic acid esters and formamidine salt is used. As a result, 5-chloro-4-hydroxy-6-methylpyrimidine can be produced in high yield.

Claims (1)

[Claims] 1. The following formula (1): 5-chloro-4-hydroxy-6-methylpyrimidine is obtained by reacting 2-chloro-3-oxobutanoic acid ester represented by the formula (wherein R represents an alkyl group) with a formamidine salt in the presence of a base. In the solvent of formamidine salt, the base and the 2-chloro-3-oxobutanoic acid ester are added at the same time while maintaining the ratio of the number of moles used.
Process for producing hydroxy-6-methylpyrimidine.