CS221135B1 - 2,6-Dimethyl-3,5-dichloro-4-hydroxypyridine ethers and their preparation - Google Patents

Abstract

The invention relates to anthelmintically active ethers of 2,5-dimethyl-3,5-dichloro-4-hydroxypyridine of the general formula in which R denotes a 4-chlorophenyl, 4-acetamidophenyl or 2-methylthio-5-pyrimidinyl group, as well as a process for the production of these substances, namely by reacting 2,6-dimethyl-3,4,5-trichloropyridine with a salt of 4-chlorophenol or 4-acetamidophenyl or 2-methylthio-5-hydroxypyrimidine with an alkali metal, in a polar aprotic solvent, such as dimethylformamide or dimethylsulfoxide, at a temperature of 120 to 160 °C, preferably at 140 to 150 °C.

Description

The invention relates to anthelmintically active ethers of 2,5-dimethyl-3,5-dichloro-4-hydroxypyridine of the general formula

in which R denotes a 4-chlorophenyl, 4-acetamidophenyl or 2-methylthio-5-pyrimidinyl group, as well as a method for preparing these substances, namely by reacting 2,6-dimethyl-3,4,5-trichloropyridine with a salt of 4-chlorophenol or 4-acetamidophenyl or 2-methylthio-5-hydroxypyrimidine with an alkali metal, in a polar aprotic solvent, such as dimethylformamide or dimethylsulfoxide, at a temperature of 120 to 160 °C, preferably at 140 to 150 °C.

The invention relates to ethers of 2,6-dimethyl-3,5-dichloro-4-hydroxypyridine of the general formula

wherein R represents a 4-chlorophenyl, 4-acetamidophenyl or 2-methylthio-5-pyrimidinyl group; the invention also relates to a process for the preparation of ethers of general formula I.

H. n.

These new, previously undescribed substances showed clear anthelmintic efficacy in an indicative evaluation (with amproil as a comparator).

In comparative experiments with the standard preparations niclosamide (N-(2-chloro-4-nitrophenyl)-5-chlorosalicylamide) and levamisole (2,3,5,6-tetrahydro-6-phenylimidazole) using the model intestinal parasites Hymenotepis nana (H. n.) in mice and Nippostriongylus brasilienslis (N. b.) in rats, the following relative values were obtained for the substances according to the invention (standard = 100%):

N.b.

2,6-dimethyl-3,5-dichloro-4-(4-chlorophenoxy)pyridine 70.8% 14.1% 2,6-dimethyl-3,5-dichloro-4- 22.9 θ/o 57.7% - (4-acetamidophenoxy) pyridine 2,6-dimethyl-3,5-dichloro-4- 60.1% 38.5% - (2-methylthio-5-pyrimidine lo-

xy) pyridine

Even with this relatively lower efficacy, the substances according to the invention are very useful for combined preparations against various helminthiasis of farm animals.

From the literature (Zajonc et al., Chim. Farm. Zhur. SSSR, 1973, Vol. 7, No. 10, p. 7) only the preparation of 2,6-dimethyl-3,5-dichloro-4-methoxypyrlidine by the reaction of 2,6-dimethyl-3,5-dichloro-4-pyridinol with diazomethane or by the reaction of the salt salt of the said compound with methyl iodide in methanol is known, but in this case, in addition to 2,6-dimethyl-3,5-dichloro-4-methoxypyridine, 1,2,6-trimethyl-3,5-dichloro-4-pyridone is also formed.

More preferred is the method for producing ethers of the general formula mentioned according to the invention, the essence of which consists in reacting 2,6-dimethyl-3,4,5-trichloropyrildiine with salts of 4-chlorophenol or 4-acetamidopheniol or 2-methylthio-5-hydroxypyrimidine with an alkali metal, in a polar aprotic solvent, such as dimethylformamide or dimethylsulfoxide, at a temperature of 120 to 160 °C, preferably at 140 to 150 °C.

The process according to the invention utilizes the reactivity of the chlorine atom at position 4 of the starting pyridine derivative; the desired compounds are obtained in good quality and in satisfactory yields.

Further details of the method according to the invention are given in the following examples, which merely illustrate the method but do not limit it in any way.

Example 1

4.14 g (0.03 mol) of p-chlorophenol are dissolved in 15 ml of methanol, 3 g of 40% aqueous sodium hydroxide solution are added with stirring and the solution is evaporated to dryness in vacuo. To the residue is added 6.3 g (0.03 mol)

2,6-dimethyl-3,4,5-trichloropyridine and 6 ml of dimethylformamide are added. The reaction mixture is heated for 1.5 h at 150 °C. After this time, it is cooled to 100 °C and decomposed by adding 60 ml of water while stirring. The precipitated crude

2,6-Dimethyl-3,5-dichloro-4-(4-chlorophenoxy)pyridine is filtered off and washed with 30 ml of water. The crude product (6.4 g, yield 70.5% of theory) is crystallized from ethanol. Melting point 150-151°C.

Example 2

4.5 g (0.03 mol) of 4-acetamidophenol are dissolved in 45 ml of methanol, 3 g of 40% aqueous sodium hydroxide solution are added, and the resulting solution is evaporated to dryness. To the obtained sodium salt of 4-acetamidophenol are added 6.3 g (0.03 mol) of 2,6-dimethyl-3,4,5-trichloropyridine, 40 ml of dimethyl sulfoxide and the reaction mixture is heated with occasional stirring for 1.5 h. at 150 °C. After this time, it is cooled to 30-40 °C, the product is dissolved in 45 ml of chloroform and filtered off from undissolved sodium chloride. The filtrate is evaporated to dryness in vacuo, the residue is stirred with 40 ml of 50% ethanol and the finely crystalline 2,6-dimethyl-3,5-dichloro-4-(4-acetamidiophenoxy)pyridine is filtered off and washed with 50% ethanol. Yield 7.55 g. Melting point after crystallization from ethanol is 229.1 to

229.7°C.

Example 3

A mixture of 2.1 g (0.01 mol) of 2,6-dlmethyl-3,4,5221135

-trichloropyridine with 1.64 g (0.01 mol) of sodium salt of 2-methylthio-5-hydroxypyrimidine is heated with 2 ml of dimethylformamide for 2 h at 140 to 150 °C. Then the reaction mixture is cooled to 100 °C, 2.5 ml of ethanol is added, cooled to 40 °C and 13 ml of water is slowly added with stirring so that initially oily 2,6-dimethyl-

Claims (2)

1. Ethers of 2,6-dimethyl-3,5-dichloro-4-hydroxypyridine of the general formula in which R represents 4-chlorophenyl-, 4-acetamithyl-3,5-dichloro-4- (2-methylthio-5-pyrimidinyloxy) After stirring at 30 DEG-40 DEG C. for 2 h, the product was filtered off and washed with 5 ml of water to yield 2 g (63.5 percent of theory), m.p. , OF THE INVENTION dophenyl- or 2-methylthio-5-pyrimidinyloxy. 2. A process for the preparation of ethers of 2,6-dimethyl-3,5-dichloro-4-hydroxypyrldine of the general formula I according to claim 1, characterized in that 2,6-dimethyl-3,4,5-trichloropyrldine is reacted with a salt. Alkali metal 4-chlorophenol or 4-acetamidorenol or 2-methylthio-5-hydroxypyrimidine, in a polar aprotic solvent such as dimethylformamide or dimethyl sulfoxide, at a temperature of 120 to 160 ° C, preferably at 140 to 150 ° C.