HU196763B - Process for production of piramidine-derivatives - Google Patents

Abstract

Condensed pyrimidine cpds. of the formula (I) and their hydrates and acid addn. salts of these cpds; and pyrimidine cpds. of the formula (IV) are new A is -(CH2)n- where n is 2, 3 or 4, or is -CH=CH-; R4 is H or opt. substd. phenyl; r is zero, 1, 2, 3 or 4, R1 is H or 1-5C alkanoyl; R2 is H, 1-5C alkanoyl or (III) R is H, 1-4C alkyl, 2-4C alkenyl, phenyl or phenyl-(1-3Cl), alkyl R3 is H; Y is halogen. Pref in (I), A is -(CH2)2- or -(CH2)3-; R4 is H or CH3; r is 1; R1 is H; R3 is H; R2 is H or -CS. NHC2H5. 7-Amino-5-imino -2, 3-dihydro -5H-thiazolo (3,2-a)pyrimidine; 8-amino-6-imino-3,4-dihydro- or 8-amino-6-imino-3-methyl- 2H,6H-pyrimido (2,1-b) (1,3)-thiazine; and N-ethyl-N1-(5-imino-2,3-dihydro-5H- thiazolo (3,2-a)pyrimidin-7-yl)thiourea are specifically specifically claimed.

Description

The present invention relates to the preparation of novel pyrimidine derivatives.

Alkyl mercaptopyrimidine derivatives having a chemically similar structure are disclosed in U.S. Pat. s. Japanese Patent Application No. C.A. 95 P 62255g (1981)] and U.S. Pat. Swiss Patent [C.A. 103 P 178 115 (1985)].

The present invention relates to a process for the preparation of pyrimidine derivatives of the formula (I) wherein:

A is -CH = CH- and

Y is halogen) such that a 2-mercapto-4,6-diaminopyrimidine of formula (11) is substituted with a dihalo derivative of formula (111) wherein Y is halogen, preferably bromine, Z is halogen, preferably chlorine; or a bromine atom and A is as defined above).

According to the process of the present invention, a 2-mercapto-4,6-diaminopyrimidine of formula (11) is reacted with a dihalo compound of formula (111). The reaction may be carried out in an inert organic solvent. As the reaction medium, e.g. dialkyl amides (preferably dimethylformamide), dialkyl sulfoxides (preferably dimethyl sulfoxide), aliphatic alcohols (e.g. ethanol or isopropanol), chlorinated aliphatic hydrocarbons (e.g. chloroform, carbon tetrachloride, dichloromethane), aromatic carbon (e.g. benzene, toluene, xylene), aliphatic ethers (e.g. diethyl ether, tetrahydrofuran or dioxane), aliphatic hydrocarbons (e.g. hexane or benzine), aliphatic ketones (e.g. acetone or methyl ethyl ketone) or mixtures thereof. It is particularly preferred to work in a medium of dimethylformamide. The reaction is carried out in the presence of an acid acceptor. For this purpose, alkali metal carbonates (e.g., sodium carbonate or potassium carbonate), alkali metal hydrogencarbonates (preferably sodium bicarbonate or potassium bicarbonate), alkali metal hydroxides (e.g. hydroxide) or tertiary amines (e.g., pyridine, trimethylamine or other trialkylamines). Preferably, sodium carbonate or potassium carbonate may act as an acid scavenger.

The starting materials (11) and (III) may be used in equimolar amounts, or 0.1-0.5 mole excess of the dihalo derivative (111) may be added to the reaction mixture.

The reaction may be carried out at a temperature of 0 ° C to 50 ° C, preferably 40 ° C to 45 ° C, depending on the reactivity of the starting materials. The reaction time is 10-20 hours. The reaction mixture is worked up in a manner known per se.

The novel compounds of formula (I) are valuable intermediates which can be converted into fused pyrimidine derivatives of formula (IV) (wherein A is as defined above) by ring closure and, if desired, subsequent acylation. The novel compounds of formula (IV) have valuable immunostimulatory properties.

The preparation of these compounds is dependent on T / 46022. Hungarian Publication Number.

The following examples further illustrate the process without limiting the invention to the examples.

Example 1

Preparation of E-2- (2-Bromo-vinyl) -thio-4,6-diaminopyrimidine

14.2 g (0.1 mol) of 2-mercapto N, 6-diaminopyrimidine and 20.4 g (0.11 mol) of 1,2-dibromomethylene (cis + → trans) in 200 cm ^{3 of} dimethylformamide 13, In the presence of 8 g (0.1 mol) of potassium carbonate for 17 hours at 45 ° C, the reaction mixture was treated with 1000 cm ^{3 of} VMI - | water. The precipitated crystals are filtered off, washed with water and dried. 11.0 g (44.5%) of the title compound are obtained. Melting point: 184-186 ° C. C ₆ H ₇ BrN ₄ S = 247.12

Anal calculated because C 29.16% 29.99% H 2.85% 3.00% N 22.67% 21.91% S 12.97% 12.83% Br 32.34% 32.32%

Example 2

Preparation of 7-Amino-5-imino-5H-thiazolo [3,2-a] pyrimidine hydrobromide hydrate

A solution of E-2- (2-bromo-vinyl) -thio-4,6-diaminopyrimidine (2.35 g, 0.05 mol) in dimethylformamide (50 ml) was stirred at 150 ° C for 20 min. The solution is then cooled to 0 ° C, the precipitated product is filtered off, washed with isopropyl alcohol and dried.

9.5 g (72%) of the title compound are obtained.

Melting point:> 300 ° C,

C ₆ H ₉ BrN ₄ OS = 265.135

Analysis calculated because C 27.18% 27.27% H 3.42% 331% N 21.13% 20.32% S 12.09% 11.75% Br 30.14% 30.84%

PATENT CLAIMS

Claims (8)

A process for preparing pyrimidine derivatives of formula (I): A is -CH = CH-, and Y is a halogen atom, characterized in that a 2-mercapto-4,6-diaminopyridine of formula (II) with a dihalate of formula (III) (in which Y is a halogen atom, preferably a bromine atom, Z is a halogen atom, preferably chlorine or bromine; and A is as defined above). Process according to claim 1, characterized in that the reaction is carried out in the presence of an acid scavenger. The process according to claim 2, wherein the acid scavenger is an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal hydroxide, an alkaline earth metal hydroxide or a tertiary amine. The process according to claim 3, wherein j c 1-21 The use of potassium carbonate or sodium carbonate as an acid binder. 5. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out in an inert organic solvent. The process according to claim 5, wherein the inert organic solvent is a dialkyl amide, a dialkyl sulfoxide, an aliphatic alcohol, a chlorinated aliphatic hydrocarbon, an aromatic hydrocarbon, an aliphatic ether, an aliphatic hydrocarbon, or mixtures thereof. 5 7. The process of claim 6 wherein the inorganic solvent is dimethyl'-formarnide. 8, 1-7. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out at a temperature of "0 to 50 ° C, preferably 40 to 45 ° C.