CS202955B1 - Method of preparing 4-hydroxypyrimidines - Google Patents

Description

The present invention provides a process for the preparation of hydroxypyrimidines by reacting a guanidine salt with an acetoacetic acid ester.

The 4-hydroxypyrimidines having the amino group at the two-position are important intermediates in the production of various fungicidal and insecticidal active substances, for example pirimiphos-methyl and pirimicarb.

Several methods for preparing hydroxypyrimidines are known in which one of the starting reactants is substituted guanidine. DOS 2,400,608 describes a process for the preparation of hydroxypyrimidines by condensation of substituted guanidines RClNHlNHg (R = NEt / NHEt) with citric acid in an acidic medium. In the first step, pyrimidinylacetic acid is formed which decarboxylates to the corresponding hydroxypyrimidine by refluxing in ethanol for 16 hours. The method is multi-stage, resource-intensive and time consuming.

In an 80% yield, the hydroxypyrimidines can be prepared by reacting the diketone with guanidines in a strong acidic medium (oleum and sulfuric acid) according to DOS 2,520,832.

Another known method for preparing hydroxypyrimidines is the object of V. Brit. No. 1,416,434, in which guanidines condense with acetic acid esters. The preparation process is carried out by adding a suspension of substituted guanidines to a solution of acetic acid esters in an inert solvent at a temperature of 128 to 132 ° C while distilling off the reaction water and the alcohol. The reaction may be carried out at a temperature of 80-170 ° C. The alkylguanidine suspension is prepared by adding alkylguanidine sulfate to a 27% alcoholic alkali metal alcoholate solution. This method, which achieves 80% yields of hydroxypyrimidines, is dependent upon the dosing of the alkylguanidine suspension at a limited temperature and the rapid removal of water from the reaction medium. Failure to observe the conditions leads to a decrease in yields due to hydrolysis of the acetic acid ester or guanidine.

A process for the preparation of 4-hydroxypyrimidines of the general formula has now been found

Γ ^Ν γ * ^Ν

NIRR ¹ ) wherein R is H, or lower alkyl of 1 to 3 carbon atoms, R 1 is lower alkyl of 1 to 3 carbon atoms, R and R are H, or lower alkyl of 1 to 4 atoms by reacting the guanidine salts of the general formula

NH = C (NH) / NRR ^{1 z} , in which R and R are as defined above with acetic acid esters of formula ( ³⁾

R ² - CO - CH - COOR ⁴ 2 3 wherein R 1 and R 2 are as defined above and R is methyl, or ethyl, in an inert solvent. It is an object of the invention to carry out the reaction at a temperature of 80 to 200 ° C, preferably 110 to 160 ° C in the presence of alkali metal carbonates. Alkali metal carbonates can be used as anhydrous, powdered or aqueous solutions.

Guanidines are used in the form of salts of mineral acids, preferably as nitrates.

As the solvent, for example, an unsaturated or preferably saturated aliphatic hydrocarbon such as cyclohexane, alkylcyclohexanes, decalin or, preferably, aromatic hydrocarbons such as benzene and its alkyl-substituted homologues, chlorobenzene, bromobenzene, chloro and bromotoluene, dichlorobenzenes and dichlorotortenes, dichlorobenzenes and dichlorobenzenes, dichlorobenzenes and dichlorobenzenes;

The product is isolated from the reaction mixture by diluting it with water and neutralizing the excess carbonate with dilute sulfuric acid. The remainder of the solvent was distilled off azeotropically or under reduced pressure. From the aqueous suspension after cooling, the product is filtered off and dried or extracted with a suitable solvent.

The novel process according to the invention is characterized in that the reaction between the guanidine salt and the acetic acid ester Ba takes place in the presence of acid-binding alkali metal carbonates. The use of carbonates will result in savings of ester and guanidine raw materials as a result of suppressing and their side reaction - hydrolysis,

Another advantage of the novel process according to the invention is the simplicity which results in a reduction of the working steps - the preparation of alcoholates and the dosing of the alkylguanidine suspension at 128 to 130 ° C are eliminated. The processes according to the invention yield products in yields exceeding 85 Z. The preparation of hydroxypyrimidines according to the invention is illustrated, but not limited, by the following examples.

EXAMPLE

Reaction mixture consisting of 44.5 g (0.226 mol) 91.72% N, N-diethylguanidine,

32.5 g (0.25 mole) of ethyl acetate, 26.5 g (0.24 mole) of powdered sodium carbonate, ml of ethyl alcohol and 100 ml of chlorobenzene are heated to the boiling point of the mixture with stirring and the ternary mixture of ethanol, water and chlorobenzene. Ethyl alcohol is removed from the distilled mixture by washing with water and the chlorobenzene is returned to the reaction. The mixture is gradually heated to 130 ° C with continuous stirring, simultaneously distilling off the lower boiling portions, washing with water and returning the chlorobenzene to the reaction mixture. This is followed by raising the temperature of the reaction mixture to 140 ° C, where the reaction mixture is maintained for 2 hours. Then the reaction mixture is cooled to below 100 ° C. The residue of chlorobenzene was distilled off from the reaction mixture under reduced pressure. The aqueous suspension of the product was cooled to 20 ° C, the product was filtered off, washed with a small amount of water and dried. 35.8 g of 98,5Z-2-diethylamino-4-hydroxy-6-methylpyrimidine m.p. t. and 134-6 ° C, which corresponds to a 86.5Z yield, calculated on N, N-diethylguanidine. Example 2

To a reaction mixture of 22.25 g (0.115 mol) of Ν, diet-diethylguanidine nitrate, 13.25 g (0.12 mol) of sodium carbonate powder, 30 ml of ethanol and 50 ml of chlorobenzene heated to boiling point, is added under stirring 16, 25 g (0.125 mole) of ethyl acetate, over 20 to 30 minutes, while distilling off the tertiary ethanol, water and chlorobenzene mixture. Ethyl alcohol is removed from the distilled mixture by washing with water and chlorobenzene. and returns to the reaction. carbinol

s.a and proceeding as in Example 1. 17.6 g of 99 7 of the product 2-diethylamino-4-hydroxy-6-methylpyrimidine are obtained, corresponding to an 85.552% yield calculated on N, N-diethylguanidine.

Example 3

To a suspension of 22.25 g (0.115 mol) of N, N-diethylguanidine nitrate, 16.25 g (0.125 mol) of ethyl acetate, in 120 ml of chlorobenzene heated to 105 DEG C., 27 g (0.066 mol) of 25.92 are added dropwise with stirring. aqueous sodium carbonate solution for 45 minutes, while distilling off the chlorobenzene, water and reacting the resulting ethanol. The separated chlorobenzene is returned to the reaction from the distilled mixture. The mixture is gradually heated to 130 ° C, while stirring and distilling off the lower boiling fractions, from which the separated chlorobenzene is returned to the reaction. The procedure is as in Example 1. 17.6 g of 2-diethylamino-4-hydroxy-6-methylpyrimidine 98.52-one are obtained, m.p. t. Mp = 134-6 ° C, which corresponds to an 85% yield.

Example 4

To a suspension of 15.1 g (0.115 M) of 94% Ν, Ν-dimethylguanidine hydrochloride, 13.25 g (0.12 M)

3 of sodium carbonate, 30 cm ethanol and 50 cm xylene heated to the boiling point of the mixture are added with stirring 17.3 g (0.12 M) of ethyl methylacetate over 20-30 minutes while distilling off the ternary mixture ethanol, water, xylene. The procedure is as in Example 1. 16.6 g of 98% 2-dimethylamino-4-hydroxy-5,6-dimethylpyrimidine are obtained, which corresponds to an 85% yield.

Example 5

To a suspension of 22.25 g / 0.115 Μ / N, N-diethylguanidine nitrate, 13.25 g / 0.12 M / carbonate

3 ml of sodium, 30 cm of ethanol and 50 cm of chlorobenzene are added with stirring 20.6 g (0.12 M) of 2-n-butyl-acetoacetate methyl over 20 to 40 minutes, while distilling off the ternary mixture ethanol, water, chlorobezene. The procedure is as in Example 1. 24 g of 2-diethylamino-4-hydroxy-5-n-butylamino-6-methylpyrimidine are obtained.

Example 6

To a suspension of 16.3 g (0.058 M) 95X of N-ethylguanidine sulfate, 13.25 g (0.12 M) sodium carbonate, 30 cm ethanol, 50 cm chlorobenzene heated to boiling, add 16.25 with stirring g (0.125 M) of ethyl acetoacetate over 20 to 30 minutes, while distilling off the ternary mixture of ethanol, water, chlorobenzene. The procedure is continued as in Example 1. 15.4 g of 972-2-ethylamino-4-hydroxy-6-methylpyrimidine are obtained.

Claims (2)

A process for the preparation of 4-hydroxypyrimidines of general formula OH N ^ N NCRR ¹⁾ wherein R is H, lower alkyl of 1 to 3 atomarai atoms, R is lower alkyl - 23 _in 1 to 3 carbon atoms, R and R are H, lower alkyl of 1 to 4 carbon atoms, by reaction of guanidine salts of the general formula NH of C / NH ₂ / NRR ¹ wherein R and r 'are as defined above, R ^2' 2 I R ^z = CO-CH Wherein R and R have the above-mentioned known acetic acid esters of the general formula COOR ^ R is methyl or ethyl in an organic inert solvent, at a temperature of 80 to 200 ° C, preferably 110 to 160 ° C, characterized in that R is methyl or ethyl. and in that the reaction is carried out in the presence of alkali metal carbonates.