JPS59227866A - Preparation of 2,4-dialkoxy-6-hydroxypyrimidines - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediated for sulfamides in high yield selectively, by hydrolyzing only one alkoxy group of a 2,4,6- alkoxypyrimidine obtained from trichloropyrimidine and an alcohol with an acid in an organic solvent. CONSTITUTION:A 2,4,6-trichloropyrimidine is reacted with an alcohol shown by by the formula ROH(R is alkyl, alkenyl, alkynyl, phenyl, or benzyl) in the presence of a base to give a 2,4,6-trialkoxypyrimidine(e.g., 5-methyl-2,4,6-trimethoxypyrimidine, etc.) shown by the formula I (X is H, alkyl, alkenly, alkynyl, phenyl, benzyl, halogen, alkoxy, alkylthio, nitro, amino, or cyano) is hydrolyzed with an acid such as hydrobromic acid in an organic solvent such as acetone, methyl ethyl ketone, etc., to give a compound shown by the formula II. USE:An intermediate for agricultural chemicals.

Description

Detailed Description of the Invention The present invention is based on the general formula (1) (wherein R represents an alkyl group, an alkenyl group, an alkynyl group, a phenyl group, or a benzyl group, and X represents hydrogen, an alkyl group, an alkenyl group, or a phenyl group). 2,4-dialkoxy-6 represented by
-Regarding a new method for producing hydroxypyrimidines.

Pyrimidines represented by general formula (1) are used in pharmaceuticals.
It is extremely useful as an intermediate in the production of sulfa drugs in the field of medicine, and as an intermediate in the production of pyrimidines having insecticidal and bactericidal activity in the agricultural field.

Conventionally, pyrimidines represented by general formula (1) have been used in pharmaceuticals,
Despite being useful as raw materials for agricultural chemicals, it is difficult to produce pyrimidines that share a hydroxyl group and an alkoxy group as substituents, and a method for diazotizing and hydrolyzing 6-amino-2,4-dialkoxypyrimidines is difficult. was taken. However, this method has a low yield and is unsuitable as an industrial production method, so the following several examples are known as improved methods.

(M is hydrogen or an alkali metal, R5 is hydrogen or an alkyl group) JP-A-49-7295 I(^)b6CJ, C, Mul, 451 (1974).

BulJ, 26 (1976)
.

(X is a lower alkoxycarbonyl group, etc.) JP-A-50-1
29577 German Patent No. 2.412.854 However, among these methods, formulas (1) and (2)
In the production method shown by formula (2), the substituent at the 5-position of the pyrimidine ring is limited to hydrogen and an alkyl group, and in the production method shown by formula (b), N-alkylation occurs simultaneously as a side reaction, resulting in the formation of an 0-alkyl compound. The production rate is not necessarily satisfactory. In addition, although the reaction shown by reaction formula (4) was carried out with the purpose of obtaining 5-cyano-2,4,6-trimethoxypyrimidine, it was not possible to obtain the desired product, and it was assumed that the reaction had changed during the post-treatment. The expected 5-cyano-2,4-dimethoxy-6-hydroxypyrimidine was obtained only as a by-product, and there is no description of the yield. Regarding this fact, it has been well known that the alkoxy groups at the 2.4 and 6 positions of the pyrimidine ring are hydrolyzed in an acidic water bath to give a hydroxyl group. However, 2.4.6-
) In the case of polysubstituted alkoxy groups such as alkoxy compounds, there is no known method for selectively hydrolyzing only <- alkoxy groups with a yield of several alkoxy groups.

Since 2,4-dialkoxy-6-hydroxypyrimidines are important intermediates for agricultural chemicals and medicines, the present inventors have intensively investigated an economically advantageous production method for 2,4-dialkoxy-6-hydroxypyrimidines, and found that the general formula (
1) Pyrimidines represented by the formula (wherein R and X are the same as in general formula (I)) are added with an acid in an organic solvent.

The present invention was completed based on the discovery that pyrimidines represented by the general formula (1) can be selectively obtained by water decomposition with a high yield.

The starting materials used in the method of the present invention have the general formula (In
These are pyrimidines represented by

These pyrimidines can be easily obtained by reacting 2.4.6-) dichloropyrimidines with TROH in the presence of a base.

Specifically, the pyrimidines include 2.4.6-trimethoxypyrimidine-2,4,6-)ethoxypyrimidine, 2.4.6-)lyisopropoquinpyrimidine,
2.4.6-) realyloxypyrimidine, 2,4,
6-)su(2-propynyloxy)pyrimidine, 2.
4.6-driphylloxypyrimidine, 2.4.6-tribenzyloxypyrimidine, 2.4.6. - ) dimethoxy-5-methylpyrimidine, 2.4.6-diisopropoxy-5-methylpyrimidine, 2.4.6-tri(2
-propynyloxy)-5-methylpyrimidine, 2.4
．． 6-) lindyloxy-5-methyv hirimicin,
2.4.6-) jetoxy-5-ethisepyrimidine,
2.4.6-) realyloxy-5-ethylpyrimidine, 2.4.6-) rifenoxy-5-ethylpyrimidine, 2.4.6-triethoxy-5-isopropylpyrimidine, 2.4.6-) (2-Propynyloxy)-5-isopropylpyrimidine, 2,4.6-1 rifhenoxy-5-isopropylpyrimidine, 2.4.6-
dribenzyloxy-5-isopropylpyrimidine, 2
．． 4.6-Drimethoxy5-Rubirimidine, 2.
4.6-)diisopropoxy-5-allylpyrimidine, 2.4.6-)su(2-propynyloxy)-5-allylpyrimidine, 2,4.6-)dibenzyloxy-
5-allylpyrimidine, 2.4.6-)lyisoproboxy-5-(2-propynyl)pyrimidine-2,4,6
-)su(2-propynyloxy)-5-(2-propynyl)pyrimidine-2,4,6-)ribenzyloxy-5
-(2-provinyl)-pyrimidine, 2.4.6-drimethoxy5-phenyl-6-hydroxypyrimidine,
2,4,6-dolylyloxy-5-phenyl-6-hydroxypyrimidine, 2,4,6-benzyloxy-5
-phenylpyrimidine/, 2.4.6-triisopropoxy-5-benzylpyrimidine, 2.4.6-diphenoxy-5-benzylpyrimidine, 2,4.6-dolylyloxy-5-chloropyrimidine, 2, 4; 5.6-
Chitramethoxypyrimidine, 2.4.6-triethoxy-5-methoxypyrimidine, 2,4.6-) diallyloxy-5-methoxypyrimidine, 214,6-driphenoxy-5-methoxypyrimidine, 2.4.6-)
Jetoxy-5-methylthiopyrimidine, 2.4.6-
)su(2-propynyloxy)-5-methylthiopyrimidine, 2,4.6-)diallyloxy-5-nitropyrimidine, 2,4.6-)liphenoxy-5-nitropyrimidine, 2.4.6- ) jetoxy-5-aminobi IJ midine, 2.4.6-) lindyloxy-5
-Aminopyrimidine, 2.4.6-) Jetoxy-5
-cyanopyrimidine, 2,4.6-driphenoxy-5
-cyanopyrimidine, etc.

The acids used in the method of the invention are mineral acids, such as hydrochloric acid,
Hydrobromic acid, etc.

The concentration of the mineral acid used is preferably higher, and concentrated hydrobromic acid is more preferable than concentrated hydrochloric acid in terms of yield.

Further, the mineral acid can be used in a catalytic amount to a large excess, but the preferred amount is in the range of 0.1 to 1 part per 1 part of the pyrimidine of the general formula (n) that is the raw material. It is.

When the treatment with these acids is carried out in an organic solvent, the yield of the pyrimidine of general formula (1) by hydrolysis is significantly improved.

Examples of the organic solvent used in the method of the present invention include ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile and propionitrile, hydrocarbons such as benzene, toluene, and xylene, tetrahydrofuran, dioxane, and diethyl ether. ethers, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric acid amide, etc., but especially acetone,
Ketones such as methyl ethyl ketone are preferred.

The reaction temperature can range from 0°G to the boiling point of the solvent, but
It is preferable to carry out the reaction at 0°C to 60°C. The product can be obtained by separating the solid precipitated after the reaction is completed.
Can be easily isolated.

The present invention will be explained below with reference to Examples.

Example 1 100m7 with reflux condenser, thermometer and stirrer!
5-methy/l/-2,4,
6"-) Rimethoxypyrimidine (577 g) was charged, and 26 ml of acetone was added to dissolve it. 47 Hydrobromic acid s
, 7 ml was added, heated under reflux for 1 hour, and then cooled to o'a. Ta.

The solid precipitated in the reaction solution was separated, washed three times with acetone, and then dried under reduced pressure to obtain 411 g of 2,4-dimethoxy-5-methyl-6-hydroxypyrimidine as a white solid. Yield: 78, mP225-227°O8 NMR (DMS O-da) δ1.72 (3H,S
), 384 (3H, s), 3.87 (?) H, S).

Example 2 1-100 with reflux condenser, thermometer and stirrer
5-Methylthio-2,4°6-drimethoxypyrimidine in a four-ml flask. Charge J9 and add acetone 20
m1 was added and dissolved. 5.0 ml of 47% hydrobromic acid
was added, heated under reflux for 3 hours, and then cooled to 0°C.

The solid precipitated in the reaction solution was separated, washed six times with acetone, and then dried under reduced pressure to obtain 2,4-simethoxy-5-methylthio-6-hydroxypyrimidine 3511 as a white solid. Yield 75%, mal 91-193°O (
d<verynp)NMn(DMso-d6)δ2.
10(3n,s), 3:q3-(3H.

S), 3.96 (3H, 8) Example 3 5-Methylthio-2,4,6-trimethoxypyridine 5. DI was charged, and 2 oml of acetone was added to dissolve it. After adding 5° Oml of concentrated hydrochloric acid and heating under reflux for 5 hours, the mixture was cooled to 0°. The solid precipitated in the reaction solution was separated, washed six times with acetone, and then dried under reduced pressure to obtain 5.099 of 2,4-dimethoxy-5-methylthio-6-hydroxypyrimidine. Yield: 66cm Example 4 5-cyano-2,4,6-)rimethoxypyrimidine s,og was charged into a 1'00d four-way flask equipped with a reflux condenser, thermometer and stirrer, and 20d of acetone was added. and dissolved. 5 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour. The solid precipitated in the reaction solution was separated, washed six times with acetone, and then dried under reduced pressure to obtain 4.45 fi of 5-cyano-2,4-dimethoxy-6-hydroxypyrimidine as a white solid. .

Yield 96%, mP24-2-244°0 (dy-e
mcp ) NMR (DM80-da) δ4.05 (S
) Examples 5 to 12 Using the raw material pyrimidines shown in Table 1, Example 1
-1: Hydrolyzed with mineral acid according to or 6.

The results obtained are shown in Table-1.

Claims (1)

[Claims] 1) General formula Ql) R (wherein, 几 represents an alkyl group, alkenyl group,
Hydrogen, alkyl group, alkenyl group, alkynyl group, phenyl group, benzyl group, norogen atom, alkoxy group,
2 (representing an alkylthio group, nitro group, amino group or cyano group). 2, which is represented by the general formula (1) (in the formula, 几 and
．． Method for producing 4-dialkoxy-6-hydroxypyrimidines.