CS224239B1 - Method of preparing 6-substituted derivatives of 5-/2-mercapto-4-oxo-3,4-dihydropyrimidin-5-yl/pentanoic acid - Google Patents

Description

The invention relates to a process for the preparation of 6-substituted 5- (2-mercapto-4-oxo-3,4-dihydropyrimidin-5-yl) pentanoic acid derivatives of the general formula I:

Ď

(i) wherein R is C 1 -C 7 alkyl, benzyl, phenyl, p-tolyl or 3,4-trimethoxyphenyl.

The compounds of formula (I), as defined above for R, can be considered both to have antimetabolite activity and to be suitable precursors for the synthesis of antitumor agents of the pyrimidine antimetabolite type. Analogously, they can be used for the synthesis of substances with anti-bacterial, antiviral and intraferonogenic activity.

The compounds of formula (I), as defined above for R, are as yet unwritten. However, they can be prepared by general procedures for the synthesis of pyrimidine derivatives.

According to the invention, the compounds of the formula I, as defined above, are prepared by condensation of the compounds of the formula II,

(Ii) _from

Wherein R has the same meaning as in formula I, with 2 to 5 mol equivalents of thiourea, preferably 3 mol equivalents, in the presence of 3 mol equivalents of sodium methylate, in the temperature range of 20 ° C to the boiling point of the reaction mixture; by saponification with an aqueous sodium hydroxide solution at a temperature of 20 to 25 ° C, and a compound of formula (I) as defined above R is released from the sodium salt solution by treatment with a mineral acid.

The condensation of thiourea with compounds of formula XI, as defined above for R, can also be carried out by the action of other strong basic agents, but the use of sodium methylate provides considerable economic, ease of handling and preparation advantages over alcoholates from higher alcohols or potassium. .

Hydrolysis of the crude condensate requires the use of mild conditions due to the possibility of side reactions, including the oxidizer. The compounds of formula (II), as defined above for R, are in part known and in part not yet described. They can all be prepared, mostly in very good yield, by the same method described for the synthesis of diethyl 2-acetyl-1,7-heptanedioate (Bourquin JP et al .: Helv.Chim.Acta 28, 528 (1945)), ie alkylation of the compounds of formula III, R ₂ -cococ ₂ h ₅ (III) wherein R is as defined above with ethyl 5-bromopentanoate.

Further details of the process for the preparation of the compounds of formula (I), the meaning of R given above, will be apparent from the following example.

5- (2-mercapto-6-methyl-4-oxo-3,4-dihydropyrimidin-5-yl) pentanoic acid

- 3 224 239

To a solution of sodium methylate prepared by dissolving 34.5 g (1.50 mol) of sodium in 500 ml of methanol at 40-45 ° C was charged with stirring 114.2 g (1.50 mol) of thiourea and then 129.2 g (0.50 mol) of 2-acetyl-1,7-heptanedioic acid diethyl ester. The reaction mixture was stirred at 20-25 ° C for 4 hours and then allowed to stand at the same temperature overnight. After distilling off the methanol under reduced pressure (water pump), the residue is saponified with 1 L of 0.5 S NaOH at 20-25 ° C for 2 hours, filtered and the filtrate acidified with dilute hydrochloric acid (1: 1) to pH 3. After cooling, the precipitate is filtered off, washed with water and dried. The material was purified by crystallization from water. Mp 243-245 ° C.

In the same manner as in Example 1, using the corresponding compounds of Formula II, the following compounds were coupled: 5- (2-mercapto-6-pentyl-4-oxo-3,4-dihydropyrimidin-5-yl) pentanoic acid, temperature mp 168-169 ° C (ethanol) 5- (2-mercapto-6-heptyl-4-oxo-3,4-dihydropyrimidin-5-yl) pentanoic acid, m.p. 150-152 ° C (ethanol + hexane) acid 5- (2-mercapto-6-benzyl-4-oxo-3,4-dihydropyrimidin-5-yl) pentanoate, m.p. 194-197 ° C (50% aqueous ethanol) 5- (2-mercapto-6- phenyl-4-oxo-3,4-dihydropyrimidin-5-yl) pentanoic acid, m.p. 195-197 ° (50% aqueous ethanol) 5- (2-mercapto-6-tolyl-4-oxo-3,4) acid 147-149 ° C (ethanol) 5- (2-mercapto-6- (3,4,5-trimethoxyphenyl) -4-oxo-3,4-dihydro-pyrimidine-) 5-yl) pentane, m.p. 202-204 ° 0 (aqueous ethanol)

Claims (1)

SUBJECT OF THE INVENTION 124 239 A process for the preparation of 6-substituted 5- (2-mercapto-4-oxo-3,4-dihydropyrimidin-5-yl) pentanoic acid derivatives of the formula X wherein R is C 1 -C 7 alkyl, benzyl, phenyl, p a tert-butyl or 3,4,5-trimethoxyphenyl group, characterized in that the compounds of the general formula (II) are condensed, h ₅ c ₂ ooc (H) - (OH ₂ ) _{4 -} OOC ₂ H ₅ (II) Wherein R is as defined above with 2 to 5 mol equivalents of thiourea, preferably 3 mol equivalents, in the presence of 3 mol equivalents of sodium methylate, ranging from 20 ° C to the boiling point of the reaction mixture, whereupon the condensate is saponified by treatment with an aqueous solution of sodium hydroxide at a temperature of 20 to 25 [deg.] C., and a compound of formula I as defined above R is released from the sodium salt solution by treatment with a mineral acid.