SU394969A1 - METHOD OF OBTAINING BIS-MORPHOLINE DERIVATIVES OF PYRIMIDINE - Google Patents

Description

one

This invention relates to the field of the preparation of new pyrimidine derivatives with valuable pharmacological properties.

Obtained by a method widely used in organic chemistry, the compounds possess a greater activity than the known compounds of a similar effect.

The proposed method for the preparation of B1 C-gorphalium pyrimidine derivatives of general HG of formula I

(T)

where 2 is an oxygen or sulfur atom; R is an alkenyl radical having up to 9 carbon atoms, or salts thereof, in that from the compound of general formula II

COOH (P)

where R is an alkyl radical containing up to 9 carbon atoms, substituted by hydroxy or goid groups, halide, hydrogen halide or water is cleaved off. The desired product is isolated in free state or in the form of a salt by known methods.

The group indicated for compounds of general formula I as an alkenyl substituent may be straight chained or branched.

Compounds of general structural formula II, containing an alkyl group substituted by ox groups, are dehydrated, for example with acetic anhydride of halo-hydrochloric acid, in particular hydrochloric, toluenesulfonic, etc., for 0.5-5

hour at temperatures between 50 ° C and so on. Kip. the reaction mixture. It is advisable to remove the water at the boiling point of the reaction mixture.

Compounds of general structural formula II, containing an alkyl group substituted by extrascale halide groups, are treated with divalent metals, in particular zinc, in an organic solvent that is inert under the reaction conditions, in particular low syirte, and temperatures between 50 ° C and so on. the reaction mixture. The halogen cleavage is carried out predominantly at the temperature of the batch reaction mixture.

Of the compounds of general formula II containing alkyl groups substituted by halide groups, the hydrogen halide is cleaved by basic reagents, such as caustic potash or sodium amide, under inertomatic conditions of reaction with an organic solvent, such as xylene, toluene or benzene, between 50 ° C C and t. Kip. The reaction is carried out at the boiling point of the reaction.

The resulting compounds of general formula I can be isolated from the corresponding reactive mixtures with the lime method, nanopiimer extraction, evaporation of the solution or with salt formation, and can also be purified by a well-known method, for example, by recrystallization or (if possible) by distillation. Of the salts, the compounds of general structural formula I can be liberated in a known manner, for example by the action of aqueous solutions, of alkali metal hydroxides.

Compounds of general formula II used as starting materials are obtained by the exchange reaction of compounds of general formula III

-Z

COOH (W)

where 2 has the indicated value, with compounds of general formula IV

R -OH (IV)

where R has the same meaning.

The compound of general formula III is expediently introduced into the reaction in the form of reactive acid derivatives, for example halides, in particular chlorides, with compounds of general formula IV, predominantly J5, an organic solvent which is inert under the reaction conditions, for example beizole, chloroform, toluene, during 1-10 hours with pagrevapii to m. bale. the reaction mixture. Preferably, the reaction is carried out for 3 hours. The reaction can also be carried out under the indicated temperature and time conditions without solvent, but it is advisable to use an excess of alcohol.

Compounds of the general formula III used as starting materials are obtained, for example, by introducing 2,4-dichloro-5-carboxy-pyrimidine into a reaction with morpholine or thiomorpholium.

The exchange reaction is carried out in organic solvents, such as toluene or benzene, for a period of 3-15 hours at a temperature between room temperature and so on. reaction mixture, sparingly for 8 hours at t. Kin. the reaction mixture in the presence of an acid binding agent, and for example triethylamine.

2,4-Dichloro-5-carboxy-pyrimidine, in turn, is prepared in its turn by the action of 2,4-dichloro-uracil-5-chlorohydride-carboxylic acid with ether.

The obtained compounds of general formula 1 at room temperature are partially solid (crystalline in appropriate case), partially liquid basic compounds, which can be reacted with the corresponding inorganic or organic acids to their acid addition salts. Particularly suitable organic acids for this are, in particular, methanesulfonic n nicrinova, and inorganic acids are hydrogen halide, nitrogen and phosphoric.

Example 1. 2,4-Bis-morpholino-5-carbisobutylenoxy-pyrimidine.

A solution of 5.3 g of 2,4-bis-morpholino-5 (-2-hydroxy-2, 2-dimethyl-ethoxycarbonyl) -nirimidip in

8 ly of acetic anhydride are heated for 3 hours under reflux to boil. The residue obtained after evaporation of the reaction mixture was dissolved in chloroform, the chloroform solution was washed out with 2N. water

with potassium carbonate solution, dried with sodium sulfate and evaporated in vacuo. 2,4-bis-morpholino-5-carbisobutyleneo-pyrimidine is obtained as a residue in the form of crystals with m.p. 69-70 ° C.

Using (2-hydroxy-2,2-dimethyl-ethyl-ester) pyrimidine 3,4-bis-morpholino-5-carboxylic acid as the starting compound is prepared as follows.

10 g of 2,4-bis-morpholino-5-carboxy-nirimidine hydrochloride are boiled for 2.5 hours with 80 ml of thionyl chloride. After distilling off the thionyl chloride, 40 ml of dry benzene are added twice and each time it is evaporated to dryness. The residue is dissolved in a mixture of 24.5 ml of 2,2-dimethyl ethylene glycol and 50 ml of absolute chloroform and then heated to reflux for 3 hours until boiling. The residue, after evaporation of the solvent, is dissolved in a small amount of water, while cooling the solution is brought to neutrality with 5N. caustic soda and thoroughly extracted with chloroform. The chloroform phase is dried with sodium sulfate and evaporated in vacuo. The residue is crystallized from ethyl ether to give (2-hydroxy-2,2-dimethyl-ethnyl-complex and ester) 2,4-bis-morpholino-5-carbopic acid ester.

The 2,4-bis-morpholino-5-carboxy-pyrimidine hydrochloride used as the starting material in this example was prepared as follows.

20 g of 2,4-dichloro-uracil-5-carboxylic acid chloride are dissolved in 120 ml of diethyl ester, then 20 ml of water is added. The reaction mixture is stirred for 1 hour at 30-35 ° C, after which the ether phase is separated, dried over sodium sulfate, filtered and evaporated at 40 ° C in vacuo. The resulting oily residue becomes crystalline on cooling and melts at 97-101 ° C.

17.3 g of 2,4-dichloro-5-carboxy-iirimidine hydrochloride thus obtained

vzmuchivayut in a mixture of 100 ml of benzene and 20 m-g

diethyl ether, then with stirring and ice-cooling, a mixture of 18.2 g of morpholine and 18.8 g of triethylamine is added dropwise. The reaction mixture is left to stand at room temperature for 15 hours, heated to 80 ° C for 1 hour and filtered while hot. The solid residue is allowed to boil with 70 liters; l of butanol. The combined filtrates are evaporated at 50 ° C. under vacuum. The oily residue is dissolved in 30 ml of methanol, then ethereal hydrochloric acid is added while cooling with ice. The 2,4-bis-morpholium-5-carboxy-pyrimidip hydrochloride crystallized out on cooling and was filtered and crystallized from a mixture of methanol and a small amount of ether. The resulting product has a double melting point of 165-170 / 225-232 ° C.

Example 2. 2,4-Bis-morpholino-5-carballyloxy-pyrimidine.

Using the method described in Example 1 and the corresponding 2,4-bis-morpholino-5 (2-hydroxy-2-methylethyloxycarbonyl) -pyrimidine starting compound, 2,4-bis-morpholino-5-carballyloxy-pyrimidine with m. Pl. 81.5 - 83.5 ° C.

Using the same method and the corresponding starting material, 2,4-bis-morpholino-5-carbobutene- (2) -oxy-pyrimidine is obtained in the form of an oil that is not distillable.

Example 3. 2,4-Bis-morpholino-5-carbisobutylenoxy-pyrimidine.

4.8 g of 2,4-bis-morpholino-5- (2-bromo-2-methyl-propoxycarbonyl) -pyrimidine is dissolved in 70 ml of isopropanol, then 1.6 g of freshly precipitated silver is added to the solution and heated at stirring until boiling for 4 hours. Next, the reaction mixture is filtered and evaporated to dryness. The residue is crystallized from diethyl chloride (petroleum ether) to give pure 2,4-bis-morpholino-5-carbisobutylenoxy-pyrimidip with mp. 68-70 ° C.

Example 4. 2,4-Bis-morpholyl-5-carbisobutyleno-pyrimidine.

5.4 g of 2,4-bis-morpholino-5-carbo- (2,3-dibromo-2-methyl-propoxy) -pyrimidine is dissolved in 60 ml of ethanol, then 0.8 g of thiourea is added. The resulting reaction mixture

warm up for 10 hours. with stirring until boiling under reflux. Then discolor the solution by means of 2 and. an aqueous solution of sodium thiosulfate and extracted with diethyl ether. The ether phase is washed with water, dissolved over sodium sulfate and evaporated to dryness. The residue is crystallized from diethyl ether (petroleum ether). The resulting 2,4-bis-morpholino-5-carbisobutenoxy-pyrimidine melts at 68-70 ° C.

The starting compounds 2,4-bis-morpholino-5-carbo- (2-bromo-2-methyl-propoxy-pyrimidine and 2,4-bis-morpholino-5-carbo {2,3- Dibromo-2-methyl-propoxy) -pyrimidine is obtained using the method described in example 1 for preparing the starting compound, replacing 2,2-dimethyl-ethylene glycol with 2-bromo-2-methyl-propanol or 2,3-dibromo-2- methyl propanol.

Subject invention

The method of producing bis-morpholine

pyrimidine derivatives of general formula I

 ABOUT

U)

 SOOK

where Z is an oxygen or sulfur atom; R is an alkeyl radical having up to 9 carbon atoms, their salts, characterized in that from the compound of the general formula II

..

 VCOOR (n)

to

where R is an alkyl radical containing up to 9 atoms. Uv carbon, substituted by hydroxy groups or

- halide groups; Z is as follows, halogen, hydrogen halide or water are split off in a known manner, followed by isolation of the desired product in the free state or as a salt with known

50 receptions.