RU2311412C1 - Method for preparing 1,3-di-[4-(6-methyl-4-pyrimidinone-2-thio)methylphenyl]adamantane - Google Patents

Abstract

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of novel 1,3-di-[4-(6-methyl-4-pyrimidinone-2-thio)methylphenyl]adamantine of the formula:

. Method involves dissolving 6-methyl-2-thiouracil in sodium hydroxide aqueous solution in the mole ratio 6-methyl-2-thiouracil : sodium hydroxide = 1:1 to yield 6-methyl-2-thiouracil S-sodium salt. Obtained salt is subjected for interaction with 1,3-di-(4-bromomethylphenyl)adamantine in the mole ratio = 2.1:1, respectively, at temperature 50°C for 60-90 min in dioxane medium. Method provides synthesis of the end product with good yield. Novel compound can be used as intermediate substance for synthesis of drugs.

EFFECT: improved method of synthesis.

3 ex

Description

The present invention relates to the field of synthesis of heterocyclic compounds, specifically to a method for producing 1,3-di- [4- (6-methyl-4-pyrimidinon-2-thio) methylphenyl] adamantane of the formula

which can find application as an intermediate for the synthesis of drugs.

A known method of obtaining substances similar in structure. When 2 moles of sodium salts of 6-R′-4-R-2-thiopyrimidines react with 1 mole of α, ω-dibromoalkanes (n = 4-10) in DMF at 60-70 ° С for 5 h, the corresponding α ω-bis (pyrimidinyl-2-thio) alkanes. (Faskhutdinov PM, Mikhailov A.S., Pashkurov P.G., Reznik BC, Ananyev E.V., Makhanko T.Yu., Gorbunov S.M. Analgesic and anti-inflammatory activity of α, ω-bis (pyrimidinyl-2- thio) alkanes.Chem.-Pharm. J. 1989, 7, p. 828).

The disadvantage of this method is the prolonged heating of the reaction mixture at sufficiently high temperatures.

The connection of the proposed structure in the literature and patent sources is not found.

The objective of the proposed technical solution is to develop a technologically advanced method for producing 1,3-di- [4- (6-methyl-4-pyrimidinone-2-thio) methylphenyl] adamantane, which allows synthesis under mild conditions.

The technical result is to obtain a new compound with a good yield.

The proposed technical result is achieved in a method for producing 1,3-di- [4- (6-methyl-4-pyrimidinone-2-thio) methylphenyl] adamantane of the formula

consisting in dissolving 6-methyl-2-thiouracil in an aqueous solution of sodium hydroxide at a molar ratio of 6-methyl-2-thiouracil: sodium hydroxide 1: 1 to obtain the S-sodium salt of 6-methyl-2-thiouracil, which is reacted with 1 , 3-di- (4-bromomethylphenyl) adamantane in a molar ratio of 2.1: 1, respectively, at a temperature of 50 ° C for 60-90 min in dioxane.

The essence of the proposed method is nucleophilic substitution of halogen atoms in 1,3-di- (4-bromomethylphenyl) adamantane with 2-thiouracil anions with the formation of the target product with a yield (53-61%)

The use of sodium hydroxide in the proposed process is necessary to convert the original 6-methyl-2-thiouracil to a water-soluble sodium salt. The high reactivity of the sodium salt allows the synthesis of compounds containing the frame structure of adamantane bound to two residues of 6-methyl-2-thiouracil. The indicated reaction time intervals were selected based on the fact that when the reaction time was less than 60 min, the required yield of 1,3-di- [4- (6-methyl-4-pyrimidinone-2-thio) methylphenyl] adamantane was not achieved, and when the reaction time is more than 90 minutes, no increase in yield is observed. When choosing a solvent for the reaction of 6-methyl-2-thiouracil with 1,3-di- (4-bromomethylphenyl) adamantane, the following requirements were taken into account: creating a homogeneous reaction mass, maintaining the required temperature and the polarity of the solvent. Dioxane meets all these requirements, all reagents are well soluble in it, it is possible to maintain a temperature of 50 ° C, and it is also sufficiently polar to generate an anion of 6-methyl-2-thiouracil in it.

The proposed method is as follows.

In an aqueous solution of sodium hydroxide, 6-methyl-2-thiouracil is dissolved in a molar ratio of 6-methyl-2-thiouracil: sodium hydroxide 1: 1 to obtain the S-sodium salt of 6-methyl-2-thiouracil, which is reacted with 1.3 -di- (4-bromomethylphenyl) adamantane in a molar ratio of 2.1: 1, respectively, in dioxane at a temperature of 50 ° C for 60-90 minutes.

Synthesis of 1,3-di- [4- (6-methyl-4-pyrimidinon-2-thio) methylphenyl] adamantane.

Example 1

0.09 g (2.1 mmol) of sodium hydroxide and 0.3 g (2.1 mmol) of 6-methyl-2-thiouracil were dissolved in 3 ml of water. 5 ml of dioxane and a solution of 0.5 g (1 mmol) of 1,3-di- (4-bromomethylphenyl) adamant in 5 ml of dioxane were added to the solution. The mixture was stirred for 60 minutes at 50 ° C. After cooling, the precipitate formed was filtered off, washed with cold water and recrystallized from ethanol. The yield of 1,3-di- [4- (6-methyl-4-pyrimidinone-2-thio) methylphenyl] adamantane 0.4 g (53%), white crystals, mp. 268-271 ° C. ¹ H NMR spectrum (DMSO), δ, ppm: 1.65-1.8 m (14Н, adamantyl), 2.15 s (6Н, СН ₃ ), 4.25 s (4Н, SCH ₂ ), 5.95 s (2Н, Н ⁵ ), 7.2-7.4 m (8H _arom ), 12.5 s (2H, NH). Found,%: N 9.30. C ₃₄ H ₃₄ N ₄ O ₂ S ₂

Calculated,%: N 9.39.

Example 2

0.09 g (2.1 mmol) of sodium hydroxide and 0.3 g (2.1 mmol) of 6-methyl-2-thiouracil were dissolved in 3 ml of water. 5 ml of dioxane and a solution of 0.5 g (1 mmol) of 1,3-di- (4-bromomethylphenyl) adamant in 5 ml of dioxane were added to the solution. The mixture was stirred for 75 minutes at 50 ° C. After cooling, the precipitate formed was filtered off, washed with cold water and recrystallized from ethanol. The yield of 1,3-di- [4- (6-methyl-4-pyrimidinone-2-thio) methylphenyl] adamantane 0.44 g (58%), white crystals, mp. 268-271 ° C.

Example 3

0.09 g (2.1 mmol) of sodium hydroxide and 0.3 g (2.1 mmol) of 6-methyl-2-thiouracil were dissolved in 3 ml of water. 5 ml of dioxane and a solution of 0.5 g (1 mmol) of 1,3-di- (4-bromomethylphenyl) adamant in 5 ml of dioxane were added to the solution. The mixture was stirred for 90 minutes at 50 ° C. After cooling, the precipitate formed was filtered off, washed with cold water and recrystallized from ethanol. The yield of 1,3-di- [4- (6-methyl-4-pyrimidinone-2-thio) methylphenyl] adamantane 0.46 g (61%), white crystals, mp. 268-271 ° C.

As follows from the presented examples, the proposed method for producing 1,3-di- [4- (6-methyl-4-pyrimidinone-2-thio) methylphenyl] adamantane is technologically advanced, it allows to obtain the specified compound in good yield.

Claims (1)

The method of obtaining 1,3-di- [4- (6-methyl-4-pyrimidinone-2-thio) methylphenyl] adamantane of the formula

consisting in dissolving 6-methyl-2-thiouracil in an aqueous solution of sodium hydroxide at a molar ratio of 6-methyl-2-thiouracil: sodium hydroxide 1: 1 to obtain the S-sodium salt of 6-methyl-2-thiouracil, which is reacted with 1 , 3-di- (4-bromomethylphenyl) adamantane in a molar ratio of 2.1: 1, respectively, at a temperature of 50 ° C for 60-90 min in dioxane.