JPH0625157B2 - Process for producing 4-hydroxypyrimidines - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing 4-hydroxypyrimidines useful as a raw material for producing pharmaceuticals, agricultural chemicals and the like.

(Prior Art and its Problems) 4-Hydroxypyrimidines are compounds also called 4-pyrimidones or 4-pyrimidinols, and are useful as raw materials for producing various compounds important as medicines, agricultural chemicals, etc. is there. 4-hydroxypyrimidines are
For example, as described in JP-A-62-67, it is used as a raw material for producing a phenoxyalkylamine derivative which is effective as an insecticide and acaricide.

General methods for producing 4-hydroxypyrimidines are described, for example, in the review DJ Brown “The chemistry of heterocyclic c
ompounds The Pyrimidines, 1962, “The chemis
try of heterocyclic compounds The Pyrimidines Supp
lementI ”1970,“ The chemistry of heterocycl
ic compounds The Pyrimidines SupplementII ”198
5 years (both John Wiley &Son's Inc., New York)
However, many other manufacturing methods are known as prior art.

Therefore, the conventional method for producing typical 4-hydroxypyrimidines and the problems thereof are described below.

4-by reaction of β-ketoesters with amidines
Method for producing hydroxypyrimidines (GWMiller and
FLRose J. Am. Chem. Soc., Vol. 82, p. 3138, 1960.
Year) (Equation 1).

This reaction may have a low yield depending on the type of amidine (eg, formamidine). Further, amidine is industrially expensive, and it is difficult to inexpensively produce 4-hydroxypyrimidines.

Method for producing 4-hydroxypyrimidines by reacting β-ketoesters with thiourea and desulfurizing the product with Raney nickel (Organic Sythesis
35, p. 1955 (Equation 2).

This method has a major drawback in that Raney nickel is generally used in a high yield but is industrially expensive and difficult to handle. Further, this method cannot introduce a substituent at the 2-position.

Method for producing 4-hydroxypyrimidines by reacting 3-amino-2-unsaturated carboxylic acid amide with acid halide or carboxylic acid ester (Japanese Patent Publication No. 48-2602)
No. 0, Japanese Patent Publication No. 48-39942) (Formula 3).

This reaction also proceeds easily, but as a 3-amino-2-unsaturated carboxylic acid amide, its production is extremely difficult except for 3-aminocrotonic acid amide, and thus it is practically difficult to use.

A method for producing 4-hydroxypyrimidines by reacting pyrimidines having a substituent at the 4-position in advance (H.
Schroeder, J. Org. Chem., 27, 2580, 1962)
(Equation 4).

However, this method requires the production of a pyrimidine having a substituent at the 4-position.

Method for obtaining 4-hydroxypyrimidine from β-ketoesters, orthoesters and ammonia (VDAdams, Sy
nthesis 1974 286) (Equation 5).

This method has a problem that the orthoester is expensive, and the yield is extremely poor when an orthoformate ester having no substituent at the 2-position is used.

4 from β-ketoester, formamide, and ammonia
-Method of obtaining hydroxypyrimidine (H. Brederck, Ber.,
90, 942, 1957) However, this method only gives 6-phenylpyrimidine in very low yields.

As a reaction similar to the present invention, a method for producing 4-hydroxyquinazolines from 2-aminoaromatic carboxylic acids such as anthranilic acid ester or anthranilic acid and formamide (US Pat. No. 3,047,462),
Similarly, 2-aminocarboxylic acid esters having a heterocycle such as 3-aminopyrazole-4-carboxyester and 2-aminothiophen-3-carboxyester can be obtained by heating with formamide to obtain bicyclic 4-hydroxypyrimidines. (Advnces in Heterocyclic Chemistr
y 38, p. 324, 1985). However, all of these compounds are very suitable for the cyclization reaction because R ₁ and R ₂ are bonded in the general formula (I), and the compounds in which R ₁ and R ₂ are not bonded are the same. The desired product was not obtained even after reacting with. According to US Pat. No. 3,950,25, 6-phenyl-4-hydroxypyrimidine is obtained from 2-aminocinnamic acid ethyl ester, but this patent only describes cinnamic acid ester. , Other derivatives are not described. In addition, although a special base such as potassium t-butoxide is used as a base and a special solvent such as dimethylsulfoxide is used, the yield is low, the reaction time is long, and it is generalized and industrially used. Not usable.

As described above, the conventional method for producing 4-hydroxypyrimidine has various problems in industrially low-cost production.

Under the circumstances, the inventors of the present invention have earnestly studied the industrial production method of 4-hydroxypyrimidines, and as a result, have completed the present invention.

The present invention provides an easily industrializable and general method for obtaining 4-hydroxypyrimidine from an acyclic 3-amino-2-unsaturated carboxylic acid ester and a carboxylic acid amide. Is a method of supplementing.

[Structure of the Invention] (Means and Actions for Solving Problems) (In the formula, R ₁ and R ₂ each represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group or an aralkyl group; R ₃ represents an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group. Represented by the formula: 3-amino-2-unsaturated carboxylic acid ester and a general formula R ₄ CONH ₂ (II) (wherein, R ₄ is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group) , An aryl group or an aralkyl group) is reacted with a carboxylic acid amide represented by the following formula in an alkanol in the presence of an alkali metal alkoxide: (Wherein R ₁ , R ₂ and R ₄ have the same meanings as defined above), and a method for producing the 4-hydroxypyrimidines.

In the above formulas (I) and (II), R ₁ , R ₂ , R ₃
And the alkyl group having 1 to 10 carbon atoms represented by R ₄ is a linear or branched alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec -Butyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group and the like.

Examples of the cycloalkyl group having 1 to 10 carbon atoms include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the like.

Examples of the aralkyl group having 1 to 10 carbon atoms include, for example,
Examples thereof include a benzyl group.

The 3-amino-2-unsaturated carboxylic acid ester represented by the formula (I) used as a raw material in the present invention is 3
-Easily produced from ketocarboxylic acid ester and ammonia (SAGlickman, J. Am. Chem. Soc., 67
Vol. 1017 p. 1946). Examples thereof include 3-aminoacrylic acid methyl ester, 3-aminoacrylic acid ethyl ester, 3-aminoacrylic acid butyl ester, 3
-Aminocrotonic acid methyl ester, 3-aminocrotonic acid ethyl ester, 3-aminocrotonic acid butyl ester, 3-amino-2-pentenoic acid methyl ester, 3
-Amino-2-pentenoic acid ethyl ester, 3-amino-2-pentenoic acid butyl ester, 3-amino-4-phenyl crotonic acid methyl ester, 3-amino-4-phenyl crotonic acid ethyl ester, 3-amino-2 -Methyl crotonic acid methyl ester, 3-amino-2-methyl crotonic acid ethyl ester, 3-amino-2-benzyl crotonic acid methyl ester, 3-amino-2-benzyl crotonic acid ethyl ester, 3-aminomethacrylic acid methyl ester , 3-aminomethacrylic acid ethyl ester, 3-amino-2-methyl-2-pentenoic acid methyl ester, 3-amino-2-methyl-2-pentenoic acid ethyl ester, 3-amino-4-methyl-2-pentene Acid methyl ester, 3-amino-4-methyl-2-pentenoic acid ethyl ester Etc. The.

Examples of the carboxylic acid amide represented by the above formula (II) used in the present invention include formamide, acetamide, propionylamide, benzamide and the like.

The amount of the carboxylic acid amides is required to be 2-fold or more moles with respect to the 3-amino-2-unsaturated carboxylic acid ester, and the reaction becomes faster as the amount of the carboxylic acid amides is used more, but in consideration of economy, it is 2 to 10-fold moles. Is preferred.

The base used in the present invention is preferably an alkali metal alcoholate (alkoxide), and examples thereof include sodium methylate, sodium ethylate, sodium butyrate, potassium methylate and potassium butyrate.

The amount of the base needs to be 2-fold or more moles with respect to the 3-amino-2-unsaturated carboxylic acid ester. It is preferably in the range of 2 to 5 times by mole.

In the present invention, if the compound of formula (I) or (II) is a liquid at the reaction temperature, the reaction proceeds without a solvent, but it is usually preferable to use a solvent. Alcohols give good results as solvents. Examples of alcohols that can be used include methanol, ethanol, propanol, isopropanol, butanol, amyl alcohol, and hexanol. These alcohols need not be the same alcohol as the alkoxide of the base used.

The alcohol used as a solvent may be a single alcohol or a mixture thereof, and the amount of the alcohol used may be 2 to 20 times the volume of the 3-amino-2-unsaturated carboxylic acid ester used. If the reaction reagent is a liquid at the reaction temperature, the reaction proceeds without using a solvent. The reaction of the present invention is 2
It can be carried out between 0 ° C and 200 ° C, preferably 90 ° C.
It is in the range of to 130 ° C. The reaction time depends on the carboxylic acid amide, the alkoxide, the concentration, the temperature, etc., but is generally about 2 to 20 hours.

The order of adding the reaction reagents is not particularly limited, but a method of adding a mixture of a 3-amino-2-unsaturated carboxylic acid ester and a carboxylic acid amide to an alcohol solution of a base is recommended.

As an example of the method for isolating 4-hydroxypyrimidines produced from the reaction mixture, an excess base is neutralized with a mineral acid such as sulfuric acid or hydrochloric acid, the produced inorganic salt is removed, and the liquid is concentrated under reduced pressure. Then, the usual method of distilling the obtained residue or recrystallizing from a suitable solvent can be adopted.

The 4-hydroxypyrimidines obtained by the present invention include 4-hydroxypyrimidine, 6-methyl-4-hydroxypyrimidine, 2-methyl-4-hydroxypyrimidine, 5-methyl-4-hydroxypyrimidine, 6-
Ethyl-4-hydroxypyrimidine, 6-benzyl-4
-Hydroxypyrimidine, 2-phenyl-4-hydroxypyrimidine, 2,6-dimethyl-4-hydroxypyrimidine, 5,6-dimethyl-4-hydroxypyrimidine, 6-ethyl-5-methyl-4-hydroxypyrimidine, 6- Ethyl-2-methyl-4-hydroxypyrimidine, 2-ethyl-6-methyl-4-hydroxypyrimidine, 5-benzyl-6-methyl-4-hydroxypyrimidine, 6-methyl-2-phenyl-4-hydroxypyrimidine, 6-ethyl-2-phenyl-4-hydroxypyrimidine, 2,5,6-trimethyl-4-hydroxypyrimidine, 6-isopropyl-4-hydroxypyrimidine and the like can be mentioned.

In the above-mentioned method for producing 4-hydroxypyrimidines according to the present invention, since the raw materials represented by the formulas (I) and (II) can be obtained at low cost, the target product can be produced at low cost, and the operation Is simple, and the target product can be obtained in high yield with less by-products.

(Examples) Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited thereto.

Example 1 Synthesis of 6-ethyl-4-hydroxypyrimidine 3-Amino-2-pentenoic acid methyl ester 12.9
g, 45.1 g of formamide, and 48.2 g of a 28% by weight sodium methoxide methanol solution were mixed and heated with stirring, and methanol was distilled off until the internal temperature reached 110 ° C.
Subsequently, the mixture was reacted at 110 ° C. for 3 hours, cooled, and quantified by high performance liquid chromatography (high performance liquid chromatography conditions: column 0DS-80Tm, 4.6φ × 25).
0 mm, detector UV 254 nm, eluent acetonitrile: water: triethylamine = 500: 500: 1 with acetic acid to pH 6.5, flow rate 1 m / min., Internal standard α
-Picoline) However, 11.4 g of 6-ethyl-4-hydroxypyrimidine was produced (yield 91.9%).
After the reaction solution was neutralized with concentrated sulfuric acid, the inorganic salt formed was removed by filtration, and the solution was heated under reduced pressure (5 mmHg) at 130 ° C. for 2 hours and concentrated. Then the residue was recrystallized from acetone to give 6
10.1 g of crystals of ethyl-4-hydroxypyrimidine
Got Melting point 131-134 [deg.] C.

Example 2 Synthesis of 6-ethyl-4-hydroxypyrimidine To 600 m of n-butanol was added 434.2 g of a 28% by weight sodium methoxide methanol solution, and the mixture was heated and the solvent was distilled off until the internal temperature reached 110 ° C. Then 3
-Amino-2-pentenoic acid methyl ester 116.3
g and formamide (141.9 g) were added dropwise over 1.5 hours, and the solvent was distilled off until the internal temperature reached 110 ° C. After heating at 110 ° C. for 2 hours, formamide 20.
Added 3 g. After that, heating was continued for another 3 hours. After cooling, analysis by high performance liquid chromatography (the conditions were the same as in Example 1) revealed that 109.1 g of 6-ethyl-4-hydroxypyrimidine was produced (yield 97.8%).

Example 3 Synthesis of 6-methyl-4-hydroxypyrimidine n-Butanol 133m to sodium metal 11.5m
g was added and heated to generate sodium butoxide, and then heated to 110 ° C. 23.0 g of 3-aminocrotonic acid methyl ester and formamide 31.5 were added to this solution.
A solution obtained by dissolving g in 50 m of n-butanol was added dropwise over 0.5 hour. The solvent was distilled off so that the internal temperature became 105 ° C, and the mixture was heated as it was for 3 hours. Here, 4.5 g of formamide was added and the mixture was further heated for 3 hours. After cooling, analysis by high performance liquid chromatography (conditions are those of Example 1).
The same) as 6-methyl-4-hydroxypyrimidine
20.3 g had been produced (yield 92.3%).

Example 4 Synthesis of 6-ethyl-2-methyl-4-hydroxypyrimidine To 90 m of n-butanol was added 72.4 g of a 28 wt% sodium methoxide methanol solution, and the mixture was heated and the solvent was added until the internal temperature reached 105 ° C. Distilled off. Subsequently, a solution of 3-amino-2-pentenoic acid methyl ester (19.4 g) and acetamide (22.2 g) in 80 m of n-butanol was added dropwise over 1 hour. During this period, the solvent distillation was continued until the internal temperature reached 110 ° C. After heating at 110 ° C. for 2 hours, the mixture was cooled to room temperature and analyzed by high performance liquid chromatography (the conditions were the same as in Example 1) to yield 18.1 g of 6-ethyl-2-methyl-4-hydroxypyrimidine. (Yield 87.1%). By treating in the same manner as in Example 1, a purified product having a melting point of 118.5 to 119 ° C was obtained. Mass spectrum M ⁺ 138.

Example 5 Synthesis of 6-ethyl-2-phenyl-4-hydroxypyrimidine To 60 m of n-butanol was added 48.3 g of a 28 wt% sodium methoxide methanol solution, and the mixture was heated and the solvent was added until the internal temperature reached 110 ° C. Distilled off. Subsequently, a solution of 12.9 g of 3-amino-2-pentenoic acid methyl ester and 30.3 g of benzamide in 60 m of n-butanol was added to 0.2 ml.
It dripped over 5 hours. During this period, the solvent distillation was continued until the internal temperature reached 110 ° C. After heating at 110 ° C. for 2 hours, it was cooled to room temperature and analyzed by high performance liquid chromatography (conditions were the same as in Example 1).
16.2 g of -phenyl-4-hydroxypyrimidine was produced (yield 81.0%). By treating in the same manner as in Example 1, a purified product having a melting point of 162 to 162.5 ° C was obtained. Mass spectrum M ⁺ 200.

Example 6 Synthesis of 5,6-dimethyl-4-hydroxypyrimidine To 45 m of n-butanol was added 36.2 g of a 28 wt% sodium methoxide methanol solution, and the mixture was heated and the solvent was distilled off until the internal temperature reached 105 ° C. did. Subsequently, a solution of 9.7 g of methyl 3-amino-2-methylcrotonate and 11.8 g of formamide in 30 m of n-butanol was added dropwise over 0.5 hour. During this period, the solvent distillation was continued until the internal temperature reached 110 ° C. After heating at 110 ° C. for 4 hours, the mixture was cooled to room temperature and analyzed by high performance liquid chromatography (the conditions were the same as in Example 1). As a result, 7.8 g of 5,6-dimethyl-4-hydroxypyrimidine was produced. (Yield 83.8%). By treating in the same manner as in Example 1, a purified product having a melting point of 206 to 207 ° C. was obtained. Mass spectrum M ⁺ 124.

Example 7 Synthesis of 6-isopropyl-4-hydroxypyrimidine To 60 m of n-butanol was added 48.3 g of a 28 wt% sodium methoxide methanol solution, and the mixture was heated and the solvent was distilled off until the internal temperature reached 110 ° C. Then 3-amino-4-methyl-2-pentenoic acid methyl ester 12.
N-Butanol 50m of 9g and formamide 45.0g
The solution was added dropwise over 1 hour. During this time, the internal temperature is 110 ° C
Evaporation of the solvent was continued until. After heating at 110 ° C. for 5 hours, it was cooled to room temperature and analyzed by high performance liquid chromatography (conditions were the same as in Example 1).
11.0 g of isopropyl-4-hydroxypyrimidine had been produced (yield 88.4%). The same post-treatment as in Example 1 was carried out to obtain a purified product having a melting point of 133.5 to 134.5 ° C. Mass spectrum M ⁺ 138.

[Effects of the Invention] When the 4-hydroxypyrimidines are produced according to the present invention, the target product can be obtained in high yield using inexpensive raw materials, and further, since there are few by-products and the operation is simple, It is very advantageous for industrially connecting 4-hydroxypyrimidines useful as a raw material for producing agricultural chemicals.

Claims (1)

[Claims] 1. A general formula (In the formula, R ₁ and R ₂ each represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group or an aralkyl group; R ₃ represents an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group. Represented by the formula: 3-amino-2-unsaturated carboxylic acid ester and a general formula R ₄ CONH ₂ (in the formula, R ₄ represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group, an aryl group). Or a carboxylic acid amide represented by the following formula: aralkyl group) is reacted in an alkanol in the presence of an alkali metal alkoxide, _(Wherein, R 1, _{R 2} and _{R 4} has the same meaning as defined above) The process for preparing 4-hydroxy pyrimidines represented by.