RU2284996C1 - METHOD FOR PREPARING 2-[n-(1-ADAMANTYL)BENZYL]THIO-6-METHYLPYRIMIDIN-4(3H)-ONE - Google Patents

Abstract

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2-[n-(1-adamantyl)benzyl]thio-6-methylpyrimidin-4(3H)-one of the formula:

that can be used as a semiproduct in synthesis of medicinal preparations. Method involves dissolving 6-methyl-2-thiouracil in sodium hydroxide an aqueous solution in the mole ratio 6-methyl-2-thiouracil : sodium hydroxide = 1:1.1 to yield 6-methyl-2-thiouracil S-sodium salt that is subjected for interaction with n-(1-adamantyl)benzyl bromide in the mole ratio = 1:1.1, respectively, at temperature 30-50°C for 15-30 min in dioxane medium, Method provides preparing indicated compound with the high yield.

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 2- (n- (1-adamantyl) thio-6-methylpyrimidin-4 (3H) -one of the formula

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

A known method for producing substances with a similar structure, S-derivatives of 2-thiouracil by reacting various 5,6-substituted 2-thiouracils with benzyl (pyridinoyl) bromides in ethanol at a boiling point of the solvent for one and a half hours, results in S-benzyl (pyridinoyl ) derivatives of 5,6-substituted 2-thiouracils. (US Pat. No. 5981537, IPC ⁶ A 61 K 31/505, C 07 D 413/00. Pyrimidine-thioalkyl and alkylether compounds / Pharmacia and Upion Co., Nugent Richard F., Schlachther Stephen T., Pa. - 1999)

A known method of producing S-derivatives of 2-thiouracil from 6-methyl-2-thiouracil in N, N-dimethylformamide in the presence of K ₂ CO ₃ at a temperature of 75-80 ° C (Novikov M.S., Ozerov A.A., Brel A.K., Navrotsky M. B., Sim OG Chemistry and technology of organoelement monomers and polymeric materials: collection of scientific works / VolgSTU. - Volgograd, 2002. - S.53-56).

These methods have significant disadvantages. Firstly, these methods do not provide a high yield of reaction products (46-73%), and secondly, prolonged heating of the reaction mixture at sufficiently high temperatures is used.

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 2- (n- (1-adamantyl) thio-6-methylpyrimidin-4 (3H) -one, which allows synthesis under mild conditions using cheap starting compounds and to obtain 2- (n- (1-adamantyl) thio-6-methylpyrimidin-4 (3H) -one in almost quantitative yield.

The technical result is to obtain a new compound with an almost quantitative yield.

The proposed technical result is achieved in a method for producing 2- (n- (1-adamantyl) thio-6-methylpyrimidin-4 (3H) -one 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: 1.1 to obtain the S-sodium salt of 6-methyl-2-thiouracil, which is reacted with n - (1-adamantyl) benzyl bromide in a molar ratio of 1: 1.1, respectively, at a temperature of 30-50 ° C for 15-30 minutes in dioxane.

The essence of the proposed method is the nucleophilic substitution of the halogen atom in n- (1-adamantyl) benzyl bromide with the anion of 2-thiouracil, with the formation of the target product in almost quantitative yield (91-97%).

The use of caustic soda in the proposed process is necessary to convert the original 6-methyl-2-thiouracil to a water-soluble sodium salt. The indicated ranges of temperature and duration of the reaction were selected based on the fact that at a temperature of less than 30 ° C and a reaction time of less than 15 minutes, the required yield of 2- (n- (1-adamantyl) thio-6-methylpyrimidin-4 (3H) - it is not achieved, and at a temperature above 50 ° C and a reaction time of more than 30 minutes, an increase in yield is not observed. The proposed method is characterized in that in the environment of dioxane from the S-sodium salt of 6-methyl-2-thiouracil anion 2-thiouracil is generated . When choosing a solvent for the reaction of 6-methyl-2-thiouracil with n- (1-adam tyl) with benzyl bromide, we took into account the following requirements: 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 30-50 ° C, and it is also sufficient it is polarized so that 2-thiouracil anion is generated in its medium.

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: 1.1 to obtain the S-sodium salt of 6-methyl-2-thiouracil, which is reacted with n- ( 1-adamantyl) benzyl bromide in a molar ratio of 1: 1.1, respectively, in dioxane at a temperature of 30-50 ° C for 15-30 minutes.

The invention is illustrated by the following examples.

Synthesis of 2- (n- (1-adamantyl) thio-6-methylpyrimidin-4 (3H) -one.

Example 1

0.46 g (11.6 mmol) of sodium hydroxide and 1.5 g (10.6 mmol) of 6-methyl-2-thiouracil are dissolved in 7 ml of water. 7 ml of dioxane are added to the solution and a solution of 1.45 g (11.6 mmol) of n- (1-adamantyl) benzyl bromide in 4.2 ml of dioxane is added dropwise. The molar ratio caustic soda: 6-methyl-2-thiouracil: n- (1-adamantyl) benzyl bromide is 1.1: 1.0: 1.1, respectively. The mixture is stirred for 15 minutes at 50 ° C. After cooling, the precipitate formed is filtered off, washed with cold water, dried and recrystallized from benzene. Yield of 2- (n- (1-adamantyl) thio-6-methylpyrimidin-4 (3Н) -one 2.5 g (97%), white crystals, mp 162-164 ° С. PMR spectrum, δ, m. d: 1.65-1.8 m (15 N, adamantyl); 2.15 s (3 N, CH ₃ ); 4.25 s (2 N, SCH ₂ ); 5. 95 s (1 H, H-5); 7.2-7.4 m ( 4H, aromatic); 12.5 s (1H, NH).

Example 2

0.46 g (11.6 mmol) of sodium hydroxide and 1.5 g (10.6 mmol) of 6-methyl-2-thiouracil are dissolved in 7 ml of water. 7 ml of dioxane are added to the solution and a solution of 1.45 g (11.6 mmol) of n- (1-adamantyl) benzyl bromide in 4.2 ml of dioxane is added dropwise. The molar ratio caustic soda: 6-methyl-2-thiouracil: n- (1-adamantyl) benzyl bromide is 1.1: 1.0: 1.1, respectively. The mixture is stirred for 20 minutes at 40 ° C. After cooling, the precipitate formed is filtered off, washed with cold water, dried and recrystallized from benzene. Yield of 2- (n- (1-adamantyl) thio-6-methylpyrimidin-4 (3H) -one 2.4 g (94%).

Example 3

0.46 g (11.6 mmol) of sodium hydroxide and 1.5 g (10.6 mmol) of 6-methyl-2-thiouracil are dissolved in 7 ml of water. 7 ml of dioxane are added to the solution and a solution of 1.45 g (11.6 mmol) of n- (1-adamantyl) benzyl bromide in 4.2 ml of dioxane is added dropwise. The molar ratio caustic soda: 6-methyl-2-thiouracil: n- (1-adamantyl) benzyl bromide is 1.1: 1.0: 1.1, respectively. The mixture is stirred for 30 minutes at 30 ° C. After cooling, the precipitate formed is filtered off, washed with cold water, dried and recrystallized from benzene. The yield of 2- (n- (1-adamantyl) thio-6-methylpyrimidin-4 (3H) -one 2.35 g (91%).

As follows from the presented examples, our proposed method for the preparation of 2- (n- (1-adamantyl) thio-6-methylpyrimidin-4 (3H) -one is technologically advanced and allows us to obtain the indicated compound in almost quantitative yield.

Claims (1)

The method of obtaining 2- (n- (1-adamantyl) benzyl) thio-6-methylpyrimidin-4 (3H) -one 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: 1.1 to obtain the S-sodium salt of 6-methyl-2-thiouracil, which is subjected to interaction with n- (1-adamantyl) benzyl bromide in a molar ratio of 1: 1.1, respectively, at a temperature of 30-50 ° C for 15-30 minutes in dioxane.