2- malonic ester, reaction with urea derivatives

Tosylation of 1146 gave 1147, which was converted to the iodo derivative, whose reaction with the sodium salt of guanine, followed by acetylation to aid its purification and then deprotection, gave 1148 (86JMC1384). The hydroxymethyl groups on C-5 of barbituric acid were introduced starting with malonic ester and then reaction with urea (93MI12). 

Diesters also react smoothly with the urea derivatives, which undergo displacement of the alkoxy groups to create amide bonds. Barbituric acid can be made this way by reaction of diethyl malonate (9.122, R=R =H) with urea (Scheme 9.64). An important family of pharmaceutical agents results from the use of substituted malonic esters. Thus, with a phenyl and an ethyl substituent the important hypnotic agent, phenobarbital (9.123) is produced. Veronal, which is another important hypnotic, is prepared from diethyl-substituted malonates. 

The method of synthesis for thousands of barbital analogs involves the reaction of urea with various derivatives of malonic acid, usually a diethyl ester of a dialkyl-substituted malonic acid. 

A very profitable engagement of Fischer was the work on derivatives of malonic and barbituric esters. In 1902 the Professor of medicine, J. von Mering, whom Fischer had met in Strassburg, and who was working in Halle/Saale, visited Fischer in Berlin. He showed him a crystalline substance he had synthesized by the reaction of phosphorous oxichloride, urea and diethylmalonic acid. It seemed to be the diethyl ester of barbituric acid and he asked Fischer to confirm the constitution of this substance. Fischer found that the structure was different. With his nephew Alfred Dilthey he found two ways to obtain it. Mering tested diethylbarbituric acid and found that it was a very active soporific substance. Fischer himself used it successfully. Other derivatives of barbituric acid also showed hypnotic properties. Fischer and Mering published their results in January 1903.2 ... 

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