HU185402B - Process for producing 5-alkyluraciles - Google Patents

Abstract

The present invention relates to an anti-viral and cytostatic 5-alkyluracil of formula (IV) wherein R is a straight or branched saturated alkyl having from 1 to 8 carbon atoms. According to the method, a fatty acid ester is reacted in a small solvent with methyl formate in the presence of at least 2 moles of sodium hydride, and an equivalent solution of thiourea is added to the reaction mixture after completion of the Claisen alignment. The solvent is then distilled off, the mixture is refluxed, the water is preferably removed by azeotropic distillation with benzene, the reaction mixture is evaporated to dryness and the residue is desulfurized with monochloroacetic acid in a manner known per se, and the product is recovered. 0 hn ^ CxcxR I II 0 * C'sN-xCH H / IY / -1-

Description

The present invention relates to a process for the preparation of 5-alkyluracils of formula IV. In the formula, R is a straight or branched saturated alkyl group having from 1 to 8 carbon atoms.

The derivatives of uracil-5-alkyl are key compounds for the synthesis of several natural mycleosides as well as their antiviral and cytostatic analogues. Practically commercially available methods for the preparation of 5-alkyl uracils can be broadly divided into two major groups [Brown, D. J., The Pyrimidines. Interscience (1962)].

One group is the process based on the selective reduction of 5-alkylbarbituric acid. Given the long reaction paths involved in these steps, it is only advantageous if cheap 5-alkylbarbituric acid is available.

Significantly more significant is the condensation of the second reaction sequence, the derivatives of the t-formyl fatty acid ester with urea or thiourea. In the latter case, the desired 5-alkyluracil is obtained by desulfurization of the resulting 5-alkyl-2-thiouracil, usually with monochloroacetic acid. The solution, which was used for the first time in more than fifty years, has been further developed by many researchers in various ways.

The use of diethyl acetals of α-formyl fatty acid esters has allowed the production of not only 5-alkyluracils but also 5-isoalkyluracils in a satisfactory yield (2328% based on the starting fatty acid) [Szabolcs A. et al., J. Láb. Comp., Y / E, 713 (1978)]. But the violent Reformatsky reaction leading to this intermediate product is difficult to accomplish on an intense industrial scale.

The condensation of the enolate of the α-formyl fatty acid ester with the urea derivative is cheaper and easier than this method.

According to this, the enolate of the α-formyl fatty acid ester is obtained by Claisen condensation of the fatty acid ester and ethyl formate in an aprotic, non-polar solvent in the presence of a base. Initially used metal-sodium base (Biirckhaltcr J.H., Scarhorough H.C., J. Am. Pharm. Assoc., 44, 545 (1955) and Johnson T.B., Hemingway E.H., J. Am. Chem. Soc., 37, 380 (1955)] proved to be superior to sodium hydride [H. Bredereck et al., Chem. Bér., 93, 1208 (1960). H. Vorbrüggen et al., Chem. Bér., 106, 3039 (1975), Coll. Czecli. Chem. Com., 41, 311 (1976)]. Upon completion of the reaction, the non-polar solvent is distilled off from the mixture, and the dry residue is dissolved in absolute ethanol at reflux condensed with thiourea and then desulfurized. This solution reduces the yields by up to 15% by extension of the 5-alkyl chain.

It is an object of the present invention to provide a process for the preparation of pure 5-alkyluracils in higher yields than previously achieved.

In our experiments, it has been found that the α-formyl compound of formula (I), wherein R is as defined above and R 'is a C 1-4 alkyl group, which is the starting material of the final product of formula (IV), 2 moles of sodium hydride are used in the reaction of the fatty acid ester and formic acid ester. (The course of this reaction is illustrated in Figure 2, where R and R 'are as defined above and R is methyl.)

According to this process, the process consists of the following sub-processes:

a) The proton of the fatty acid ester dissociates by an electron-withdrawing action of the adjacent carbonyl group in a equilibrium reaction characterized by a constant pK _s .

b) The anion of the fatty acid ester is added to the most polar carbonyl group in the system, the formic acid ester.

c) ill. d) The resulting semi-acetal anion is converted into an enolate anion in a two step equilibrium process characterized by a pK-2 constant, while losing a proton and an alkoxide anion.

e) Protons in the system are neutralized by sodium hydride.

Because usually pK! > pK ₂ and the reaction indicated by b in Figure 2 is the slowest step, the gross reaction rate is determined by the pH of the system through equilibrium "a", because the concentration of dcprotonated fatty acid anions depends. If pK | greater than the pK of the alcohol leaving steps c, d, as is the case for the esters of aliphatic monocarboxylic acids, complete removal of the alcohol to an alkoxide is necessary to form the fatty acid ester anion in sufficient concentration in the reaction mixture. Thus, the theoretical sodium hydride consumption of 1 mole of fatty acid ester according to reaction equation A is 2 moles, as opposed to 1-1.25 moles suggested in the prior art.

Addition b, which determines the gross rate of the process, depends on the polarity and spherical availability of the carbonyl formic acid ester. Therefore, it is preferable to use methyl formate instead of ethyl formate. The disadvantage of the known processes, that the unstable α-formyl fatty acid ester enolate (I) formed in reaction A (Figure 1), even during gentle laboratory vacuum evaporation, trimerizes to an aromatic by-product, is eliminated by Claiscn. In an apolar aprotic solvent for condensation, an absolute alcoholic solution of thiourea was added to convert the sensitive sodium salt (I) to a non-trimerizing thioureido compound (II) (Reaction B).

The water formed in reaction C was then removed from the system as an azeotropic benzene, thereby completing the cyclization of the thioureido compound (11).

Finally, the alkylthiouracil of formula (III) was converted to the (IV) -5-alkyl nracil by reaction with monochloroacetic acid (reaction "D").

The following examples illustrate the invention without limiting it.

Examples

Example 1: Preparation of 5-ethyluracil

To a suspension of 100 g (2.1 mol) of a 50% paraffin oil sodium hydride dispersion in 1000 ml of absolute ether (in a 2 L four neck flask equipped with stirrer, reflux and thermometer) was added 133 ml of butyric acid ethyl acetate (1 mol) and 1.5 mol) of a mixture of methyl formate under vigorous stirring. After 24 hours, the reaction mixture was diluted with a solution of methyl formate (30 mL, 0.5 mol) in absolute ether (500 mL). After stirring for another 24 hours, the evolution of gas was complete and the reaction was complete.

At this time, 100 mL of absolute ethyl alcohol was added to the vessel to quench the excess sodium hydride and the mixture was stirred for half an hour. Thereafter, 76 g of thio-21 were added

After the addition of 185 402 urea (1 mol) and 700 ml of absolute alcohol, the ether was distilled off with a 30 cm Vigreux column at atmospheric pressure from the resulting thioureido compound with continuous addition of 500 ml of absolute alcohol over four hours. The mixture was then refluxed for 16 hours at an internal temperature of 75 ° C, 200 ml of absolute benzene were added and the water formed in reaction C was azeotroped using the same column and the reaction mixture was heated to 120 ° C in an oil bath. 1 θ was evaporated to dryness over four hours. The dry residue was dissolved in 700 ml of hot water, shaken with 200 ml of light petroleum (Fp 120 ° C) and then washed with 100 ml of hot water. For the aqueous phase, 0.1 g of charcoal and 160 ml of cc were hot. hydrochloric acid was added and filtered quickly. The filtrate was refluxed with 105 g (1.1 mol) of monochloroacetic acid for 3 hours. After cooling the solution, the precipitated 5-ethyluracil was filtered off, washed on the filter and dried.

Production: Analysis: 99.6 g (0.716 mol) 71.6% N S 20 C C calculated (%) 51.4 5.7 20.0 Φ found 25 (%) 52.0 5.9 20.1 Φ

M.p. 3110-315 ° C

Example 2: Preparation of 5-isopropyl uracil

All of the procedures described in Example 1 were followed except that instead of the ethyl ester of butyric acid

Starting from 149.5 ml (1 mol) of ethyl isovaleric acid and using the same amount of absolute tetrahydrofuran instead of ether as the reaction solvent.

Yield: 56.1 g (0.364 mol) 36.4%

Analysis: C H N S 40 date: (%) 54.5 6.5 18.2 Φ found: (%) 54.9 6.7 18.1 Φ · 45

308-312 ° C (staring).

Example 3: Preparation of 5-hexyluracil

In all of the above procedure, except that instead of butyric acid ester, starting from 198 ml (1 mol) of ethyl acrylic caprylic acid, the reaction was run twice. The dry residue from the third step was dissolved in 700 mL of hot water, extracted with 200 mL of petroleum ether (b.p. 120 ° C), which was then washed with 100 mL of hot water. 105 g (1.1 mol) of monochloroacetic acid and 160 ml of cc are added to the aqueous phase. hydrochloric acid was added and refluxed for 8 hours. After cooling, the precipitated material was filtered off, washed and then recrystallized from ethyl alcohol. Yield: 103, g (0.525 mol) 52.5%

Analysis: C H N S date: (%) 61.2 8.2 14.3 Φ bowl: written (%) 61.7 8.3 14.1 Φ

272-275 ° C (staring).

Claims (2)

A process for the preparation of 5-alkyluracils of formula IV wherein R is a linear or branched saturated alkyl group of C 1-8 atoms in an aprotic solvent from a fatty acid ester of formula I wherein R is as defined above and R 'is C 1-4 alkyl - starting from α-forynyl fatty acid ester enolate and thiourcidic acid moiety, distilling off the solvent, refluxing the mixture, removing the water, evaporating the mixture to dryness, remainder with monochloroacetic acid, wherein R and R 'are as defined above, in the presence of at least 2 moles of sodium hydride, and after completion of Claisen condensation, an equivalent amount of an alcoholic solution of thiocarbamide is added and the resulting water is removed by azeotropic distillation. Process according to claim 1, characterized in that the azeotropic distillation is carried out with benzene.