DE1145622B - Process for the preparation of 5-alkoxy-2-aminopyrimidines - Google Patents

Description

Process for the preparation of 5-alkoxy-2-aminopyrimidines It is known to condense malondialdehyde with guanidine to form 2-aminopyrimidine. It was to expect that 2-alkoxy-malondialdehydes are analogous to the corresponding 5-alkoxy-2-aminopyrimidines would condense.

The 2-alkoxymalondialdehydes required for this were used for the first time from 1,2-dialkoxyethene and N-methylformanilide by Vilsmeier condensation in the presence made of phosphorus oxychloride, initially the ß- (N-methylanilino) -a-alkoxyacrolein arises, which is then acid hydrolyzed to 2-alkoxymalondialdehyde. There now the 1,2-dialkoxyethene in turn only comes from the easily accessible 1,1,2-trialkoxyethane produced in a known manner by catalytic cleavage of a mole of alkanol must be, so result from trialkoxyethane to 2-alkoxy-malondialdehyde three synthesis steps with a total yield of only about 150/0 of theory.

While the direct conversion of acetals and alkyl acetals according to Vilsmeier with the intermediate product formed from 1 mol of phosgene with dimethylformamide according to Z. Arnold and F. Norm, "Chemicke Listy", vol. 51 (1957), p. 1082, in good yield succeeds, it was found that the corresponding reaction with the alkoxyacetals (= 1,1,2-trialkoxyethanes) did not materialize because its methylene group presumably did not have the required reactivity having.

It has now been found that, surprisingly, with a simple process, the 1,1,2-trialkoxyethanes of the general formula can be obtained directly in good yield where R is a low molecular weight alkyl radical, to the technically useful 5-alkoxy-2-aminopyrimidines of the general formula if the 1,1,2 trialkoxyethanes are reacted with an acidic halogen-containing condensation agent suitable for the Vilsmeier reaction, for example with phosgene, phosphorus pentachloride, phosphorus oxychloride or thionyl chloride at temperatures of up to 70 ° C, whereby - in contrast to the procedure according to Arnold and Sorm - one of the two l-alkoxy groups of the 1,1, 2-trialkoxyethanes is exchanged for halogen and by subsequent or simultaneous addition of a formamide of the general formula where R1 is a low molecular weight alkyl group and R2 is a low molecular weight alkyl group or a phenyl group, the Vilsmeier reaction is carried out in the temperature range mentioned above and the resulting reaction mixture is immediately reacted with a solution of a guanidine salt and alkali metal alkanolate or potassium hydroxide in a lower alcohol.

If phosgene is used as a condensing agent analogous to those listed above Applied literature references, the yields are very low; on the other hand is sufficient z. B. 1 hour introduction of excess phosgene into a solution of 1,1,2-trimethoxyethane in chlorobenzene at 70 "C in the presence of the dimethylformamide required for the condensation, one of the two l-methoxy groups of 1,1, 2-trimethoxyethane with cleavage of chlorocarbonic acid methyl ester is exchanged for a chlorine atom and the Vilsmeier reaction takes place, and cooking the reaction mixture with Guanidine nitrate in methanolic sodium methylate solution to directly in a yield of 400/0 of Theory to get 5-methoxy-2-aminopyrimidine.

Phosphorus pentachloride has proven to be even more expedient for the implementation as a condensing agent, of which 1 mol to 1 mol of 1,1,2-trimethoxyethane at 60 "C lets act until it dissolves. Here too, one of the two l-methoxy groups is used exchanged for chlorine atoms to form methyl chloride and 1 mole of phosphorus oxychloride, that for the Vilsmeier reaction that now follows with the dropwise addition of dimethylformamide is required. Here, too, the reaction mixture becomes direct after the reaction has ended registered in a solution of guanidine carbonate in methanolic sodium hydroxide solution and heated. 5-Methoxy-2-aminopyrimidine is then obtained in a yield of about 60 per cent of theory.

The 5-alkoxy-2-aminopyrimidines which can be prepared extremely efficiently by this process serve primarily as intermediate products for the production of valuable sulfonamides with new features.

Example 1 In a mixture of 120 g (1 mol) 1,1,2-trimethoxyethane, 182.5 g (2.5 mol) of dimethylformamide and 600 ml of chlorobenzene are introduced into phosgene, the reaction temperature increasing to 600 ° C. in the course of about half an hour increases and then gradually decreases again. With further introduction of phosgene the reaction mixture is now in the water bath for another hour at one Maintained temperature of 70 "C. The brown reaction solution, which is then cooled, is now added dropwise with stirring and ice cooling into a mixture of 540 g (10 mol) dry sodium methylate 244 g (2 mol) of guanidine nitrate in 11% of absolute methanol, a reaction temperature of 20 to 30 ° C. is maintained The dropwise addition is stirred for a further 15 minutes at room temperature, then the methanol distilled off with stirring on the steam bath and then another 1 hour in the boiling Reheated water bath. The cooled residue is until the salts dissolve with Stirred water, separated the chlorobenzene layer, and the aqueous phase several times extracted with chloroform, and the combined chlorobenzene and chloroform extracts are dried with potassium carbonate. After the chloroform has been distilled off, the The residue is distilled in a water jet vacuum. First of all, a forerun is cut off, which contains the chlorobenzene and dimethylformamide. Then 50 g (= 4001o of theory) 5-methoxy-2-aminopyrimidine (bp 13 = 133 to 135 ° C) over, which after the Solidifying has a melting point of 80 to 83 "C; after dissolving this crude product 5-methoxy-2-aminopyrimidine is obtained in a little water and precipitation with saturated sodium chloride solution in colorless crystals with a melting point of 85 to 87 "C.

Example 2 120 g of 1,1,2-trimethoxyethane are ice-cooled with stirring and moisture exclusion slowly mixed with 210 g (about 1 mol) of phosphorus pentachloride, so that the reaction temperature does not exceed 30 ° C. The mixture is then stirred 75 It is heated to 60 ° C. for minutes. After cooling, 225 mol (about 3 mol) of dimethylformamide are added added dropwise with stirring, the reaction temperature being increased to 10 by cooling with ice to 20 "C. This is followed by 1/2 hour at room temperature and then Stirred for a further 45 minutes at 70 ° C. After cooling, it is added to the reaction mixture added dropwise with ice cooling 1 1 of methanol, the reaction temperature 10 to 20 "C should not exceed. Then, also with cooling, at a reaction temperature from 20 to 30 "C 280 g (about 11 mol) of powdered, technical sodium hydroxide and then 180 g (1 mol) of guanidine carbonate are stirred in. Thereafter, the reaction mixture Stirred for 15 minutes at room temperature, then the methanol also under Stirring distilled off on the steam bath and then another 1 hour at the same bath temperature touched.

After cooling, the residue is dissolved in about 1.2 l of ice water and extracted several times with chloroform. The combined chloroform extracts are with Sodium sulfate dried and then the chloroform at normal pressure and finally the dimethylformamide is distilled off in a water jet vacuum. Finally distill 70 g (= 56% of theory) 5-methoxy-2-aminopyrimidine (boiling point 12 = 130 to 1330 C) over. The crude product with a melting point of 81 to 84 ° C. is recrystallized from benzene. The pure product melts at 86 to 87 "C.

Example 3 According to Example 2, 162 g (1 mol) of 1,1,2-triethoxyethane are obtained implemented and processed. This is obtained after distillation in a steam jet vacuum 72.7 g (= 53% of theory) 5-ethoxy-2-aminopyrimidine (bp 4 ~ s = 122 to 125 "C), which melts at 109 to 112 ° C after solidification. The crude product is made from benzene recrystallizes and then melts at 114 to 115 "C.

Example 4 196 g of 1,1,2-tri-n-propoxyethane are added with cooling 210 g of phosphorus pentachloride are added at 20 to 25 "C. The mixture is then still Stirred for 1/2 hour at room temperature. Subsequently, with cooling at 20 to 25 "C 225 ml of dimethylformamide are added dropwise. The mixture is then about 70 minutes heated to 70 ° C. After cooling, 500 ml of methanol are added dropwise with cooling. This solution is then powdered at 20 to 25 ° C. to form a suspension of 240 g Caustic soda was added dropwise to 800 ml of methanol and stirred for another 1/2 hour. In addition ß-dimethylamino-a-n-propoxyacrolein now present in the solution in addition to inorganic salts 200 g of guanidine nitrate and then 70 g of caustic soda are now given. Thereafter the methanol is distilled off with stirring. The distillation residue is with Add 1.5 l of water and stir until all the salts have dissolved. The received Solution is extracted with chloroform. After concentrating the chloroform extracts the distillation residue on the water jet pump at a pressure of 12 mm of mercury distilled. This gives 86 g of 2-amino-5-n-propoxypyrimidine (Bp = 145 to 1500C, m.p. = 73 to 75 "C).

EXAMPLE 5 196 g of 1,1,2-triisopropoxyethane become analogous Way 120 g of 2-amino-5-isopropoxypyrimidine (bp 12 = 138 to 142 "C, m.p. = 74 to 75 ° C).

Example 6 From 238 g of 1,1,2-tri-n-butoxyethane, as in example 4 stated, 100 g of 2-amino-5-n-butoxypyrimidine (b.p. 12 = 158 to 1600 ° C., melting point = 73 up to 75 "C).

Example 7 The same amount is obtained from 238 g of 1,1,2-triisobutoxyethane 130 g of 2-amino-5-isobutoxypyrimidine (bp 12 = 155 to 158 "C, mp = 66 to 67" C).

Example 8 120 g of 1,1,2-trimethoxyethane are added with stirring, ice cooling and moisture exclusion slowly mixed with 383 g of phosphorus oxychloride so that the reaction temperature does not exceed 30 ° C. This is followed by about 30 minutes stirred at room temperature. Then in the cooled mixture with cooling 225 ml of dimethylformamide were added dropwise at 20 "C., stirred for 1/2 hour at room temperature and then slowly increased the internal temperature and finally 45 minutes at Held at 600 C. Then 500 ml of methanol are added dropwise to the reaction mixture, the reaction temperature being kept at about 20 ° C. by cooling with ice. Thereafter 200 g of guanidine nitrate are stirred in and finally also under good Cooling, whereby the temperature should not exceed 30 "C, with 1000 ml of 4 n-methanolic Sodium hydroxide solution adjusted to pH 8 and additionally mixed with 64 g powdered caustic soda. The methanol is then distilled off with stirring and the residue that remains stirred for 1 hour in a boiling water bath. After cooling, the residue becomes dissolved in 400 ml of water and extracted several times with chloroform. The United Chloroform extracts are dried over sodium sulfate and then the chloroform at normal pressure and the dimethylformamide is distilled off in a water jet vacuum. In the end distill 40 g (= 330/0 of theory) 2-amino-5-methoxypyrimidine (b.p. 12 = 136 to 138 "C) with a melting point of 83 to 85" C above.

From the distillation residue are recrystallized with Carbon tetrachloride still another 5.3 g of 2-amino-5-methoxypyrimidine, melting point 80 to 82 "C obtained.

In an analogous manner, but in a lower yield, 2-amino-5-methoxypyrimidine is obtained, if thionyl chloride is used instead of phosphorus oxychloride.

Claims (2)

PATENT CLAIMS: 1. Process for the preparation of 5-alkoxy-2-aminopyrimidines of the general formula wherein R is a low molecular weight alkyl group, from 1,1, 2-trialkoxyethanes of the general formula in which R has the meaning given, characterized in that the 1,1,2-trialkoxyethanes are reacted with an acidic, halogen-containing condensing agent suitable for the Vilsmeier reaction at temperatures up to 70 ° C., one of the two l-alkoxy groups being exchanged for Halogen takes place, and that by simultaneous or subsequent addition of a formamide of the general formula where R1 is a low molecular weight alkyl group and R2 is a low molecular weight alkyl group or a phenyl group, the Vilsmeier condensation takes place in the above-mentioned temperature range and the resulting reaction mixture finally reacts with a solution of a guanidine salt and alkali hydroxide or alkali alkanolate in a lower alcohol. 2. The method according to claim 1, characterized in that as halogen-containing Condensing agent phosgene or phosphorus pentachloride is used. Considered publications: "Chemistry and Industry", Vol. 48, 1956, p. 1453; "Collection of Czechoslovak Chemical Communique", Vol. 23, 1958, 5. 452off., And Vol. 24, 1959, pp. 1667 to 1671.