CS195210B1 - Process for preparing 2-methylthio-5-hydroxypyrimidine - Google Patents

Abstract

The invention relates to a process for the production of 2-methylthio-5-hydroxypyrimidine by demethylation of 2-methylthio-5-methoxypyrimidine with aluminum chloride in an anhydrous organic solvent. 2-methylthio-5-hydroxypyrimidine is the main intermediate in the production of the known antifungal agent 2-methylthio-5/3-iodopropargyloxy/pyrimidine

Description

The present invention relates to a process for preparing 2-methylthio-5-hydroxypyrimidine by demethylating 2-methylthio-5-methoxypyrimidine with aluminum chloride in an anhydrous organic solvent. 2-Methylthio-5-hydroxypyrimidine is a major intermediate in the manufacture of the known antifungal 2-methylthio-5 (3-iodopropargyloxy) pyrimidine.

The demethylation of 2-methylthio-5-methoxypyrimidine to give 2-methylthio-5-hydroxypyrimidine is the subject of Ss. No. 184103, according to which the reaction is carried out with aluminum chloride in an organic solvent at elevated temperature and the resulting 2-methylthio-5-hydroxypyrimidine is isolated by pouring the reaction mixture into excess ammonia, filtering off the precipitated aluminum hydroxide and concentrating to crystallize. In the manner described in the above-mentioned cf. however, 2-methylthio-5-hydroxypyrimidine from 2-methylthio-5-methoxypyrimidine can only be obtained with the use of a high-quality but hardly definable chloride. aluminum. It is not known reliable analytical method, respectively. criteria for assessing the applicability of a particular aluminum chloride for this reaction.

It has been shown that some aluminum chloride, despite the relatively high chlorine content (93-99 percent of theory), gives low yields of 2-methylthio-5-hydroxypyrimidine and, at times, does not react with 2-methylthio-5-methoxypyrimidine at all. It would therefore be necessary to carry out experimental demethylation with each new batch of aluminum chloride, which is uneconomical.

It has now been found that practically any anhydrous and ² sublimed commercial grade aluminum chloride can be used for demethylation if 2-methylthio-5-methoxypyrimidine is converted at least partially or completely to the hydrochloride prior to demethylation.

The process according to the invention is preferably carried out by introducing into the solution of 2-methylthio-5-methoxypyrimidine in a suitable organic solvent, such as benzene or 1,2-dichloroethane, freed of moisture by azeotropic distillation, 0.5 to 1 mol of hydrogen chloride gas per 1 mol of 2-methylthio-5-methoxypyrimidine, then aluminum chloride is added and the reaction mixture is heated to 50-90 ° C. After demethylation was complete, the reaction mixture was quenched and the precipitated 2-methylthio-5-hydroxypyrimidine separated by filtration and washed with water.

The process according to the invention thus makes it possible to use anhydrous aluminum chloride of commercial quality, whereby the isolation of the product is also considerably simpler. This eliminates the lengthy filtration of aluminum hydroxide and the difficult to reproduce thickening of the filtrate.

The process according to the invention is shown in the following examples which illustrate the process but do not limit it. Examples

Example 1

A solution of 234 g (1.5 mol) of 1-methylthio-5-methoxypyrimidine in 2200 ml of dry 1,2-dichloroethane is saturated with 27.3 g (0.75 mol) of dry hydrogen chloride. While stirring, 435 g (3.26 mol) was added at 20 ° C. The mixture was heated to 80 ° C with stirring and maintained at this temperature until the evolution of methyl chloride had ceased for 45-50 minutes. After cooling to 40 ° C, the reaction mixture was carefully decomposed with stirring 1550 ml of water and stirred.

h at 10-15 ° C. The excreted product is. aspirate and wash with 2 x 400 ml water. The yield of crude (94.5%) 2-methylthio-5-hydroxypyrimidine is 146.8 g (65.15% of theory).

After crystallization from water, the product had m.p.

178 DEG-180 DEG.

Example 2

A solution of 117.1 g (0.75 mol) of 2-methylthio-5-methoxypyrimidine in 1100 ml of dry dichloroethane is saturated with 13.66 g (0.375 mol) of dry HCl. Stirring is added 217.5 g (1.63 mol) of anhydrous. aluminum chloride / 99% by weight of Cl ^- / »reaction mixture is heated to boiling until escapes methyl chloride, which takes 30 to 40 minutes. After cooling to 40 DEG C., the reaction mixture is carefully quenched with 750 ml of water while cooling and stirred at 10-15 DEG C. for 1 hour. The resulting crude 2-methylthio-5-hydroxypyrimidine was filtered off with suction and washed with 2 x 200 ml of water. The yield was 69.4 g (content 95.5%), which is 62.2% of theory.

Example 3

A solution of 32 g / 0.2 mole / of 2-methylthio-5-methoxypyrimidine in 300 ml of dichloroethane, dehumidified by azeotropic distillation, AE saturated with 7.3 g /0.2 mole / of dry HC1 and stirring at ²⁰ ° C 59.5 sprinkled into the mixture g bezv. aluminum chloride (93% Cl 'content) so that the temperature did not exceed 35 ° C. The resulting solution was heated to boiling with stirring until methyl chloride escaped (ca. 30-40 min). The reaction mixture was cooled to 40 ° C and quenched with 214 mL of water. After stirring at 10-15 ° C for one hour, the precipitated product is collected by filtration and washed with 100 ml of water. The yield of crude 2-methylthio-5-hydroxy-pyrimidine (95% purity) was 19 g, i.

65.3% of theory.

Example4

A solution of 234 g (1.5 mol) of 2-methylthio-5-methoxypyrimidine in 2200 ml of dichloroethane, freed of moisture by azeotropic distillation, is saturated with 40.5 g (1.125 mol) of dry hydrogen chloride. While stirring at 20 ° C, 435 g (3.26 mol) is added. aluminum chloride (93% Cl) and the reaction mixture was heated to 80 ° C until the evolution of methyl chloride ceased (50 min). After cooling to 40 ° C, the dark solution is quenched with 1550 ml of water, cooled to 15 ° C and stirred for 1 h. The precipitate formed is filtered off with suction and washed with 800 ml of water. The yield of crude 2-methylthio-5-hydroxypyrimidine is 145 g (64.5% of theory).

Claims (1)

SUBJECT V A process for the preparation of 2-methylthio-5-hydroxypyrimidine by demethylation of 2-methylthio-5-methoxypyrimidine with anhydrous aluminum chloride in an anhydrous inert organic solvent capable of forming an azeotropic mixture with water, for example benzene, toluene or xylene or chloroform, Tetrichloromethane or 1,2-dichloroethane, at elevated temperature, preferably at the boiling point of the reaction mixture, characterized in that 2-methylthio-5-methoxypyrimidine, converted at least at the starting point, is used as starting material. 50% to form the hydroxy chloride. Severography. n. p ^ Introduction 7, Moat