Malonic 2- -, diethyl esters

Preparation 202.—Diethyl Malonate [Diethyl ester of yrroy>an-diadd ... 

Epilepsy is a disease that is characterized hy recurring convulsive seizures. Phenoharhital, 58, possess specific usefulness in epilepsy. In general, harhituric acid derivatives are synthesized from phenylethyl-malonic diethyl ester [8]. 

Tetrahedral intermediates have been shown to be kinetically important in the S->N transfer reaction of S-acetylmercaptoamine (Martin and Hedrick, 1962) the O N transfer reaction of 0-acetylethanolamine (Hansen, 1963), intramolecular-aminolysis of ethyl y-aminobutyrate, ethyl 8-aminovalerate, and related reactions (Martin et al., 1964), hydrolysis of thiazolines (Martin et al., 1959 Martin and Parcell, 1961a Schmir, 1965), hydrolysis of oxazolines (Martin et al., 1964 Greenhalgh et al., 1963 Martin and Parcell, 1961b), hydrolysis of 2-imidazolines (Harnsberger and Riebsomer, 1964), and in the hydrolysis of acetyl-malonate diethyl ester (Lienhard and Jencks, 1965). 

Physical Properties. Industrially, the most important esters are dimethyl malonate [108-59-8] and diethyl malonate [105-53-3] whose physical properties are summarized in Table 2. Both are sparingly soluble in water (1 g/50 mL for the diethyl ester) and miscible in all proportions with ether and alcohol. 

Hydrochloric acid [7647-01-0], which is formed as by-product from unreacted chloroacetic acid, is fed into an absorption column. After the addition of acid and alcohol is complete, the mixture is heated at reflux for 6—8 h, whereby the intermediate malonic acid ester monoamide is hydroly2ed to a dialkyl malonate. The pure ester is obtained from the mixture of cmde esters by extraction with ben2ene [71-43-2], toluene [108-88-3], or xylene [1330-20-7]. The organic phase is washed with dilute sodium hydroxide [1310-73-2] to remove small amounts of the monoester. The diester is then separated from solvent by distillation at atmospheric pressure, and the malonic ester obtained by redistillation under vacuum as a colorless Hquid with a minimum assay of 99%. The aqueous phase contains considerable amounts of mineral acid and salts and must be treated before being fed to the waste treatment plant. The process is suitable for both the dimethyl and diethyl esters. The yield based on sodium chloroacetate is 75—85%. Various low molecular mass hydrocarbons, some of them partially chlorinated, are formed as by-products. Although a relatively simple plant is sufficient for the reaction itself, a si2eable investment is required for treatment of the wastewater and exhaust gas. 

DIETHYL ACETAMIDOMALONATE (Malonic acid, acetamido-, diethyl ester)... 

The starting material is prepared by reacting 2-amino-6-methylpyridine with ethoxymethyl-ene-malonic acid diethyl ester and then reacting that product with sodium hydroxide. 

Ethoxymethylene malonic acid diethyl ester Diethyl sulfata... 

The starting material may be produced by reacting 6-amino-2-methylthiopyrimidine with ethoxymethylene malonic acid diethyl ester. The intermediate thus produced is converted by boiling in diphenyl ether to 6-ethoxycarbonyl-2-methylthio-5-oxo-5,B-dihydropyrido-[2,3-d]pyrimidine. That is hydrolyzed by sodium hydroxide to cleave the ethoxy group and then ethylated with diethyl sulfate to give the starting material. 

Nit ropheny I) pyridine Ethoxymethylene malonic acid diethyl ester Ethyl iodide Sodium hydroxide... 

MalONIC ACID, ETHYLHYDROXY, DIETHYL ESTER, BENZOATE, 45, 37 Mfsitaidehydf, 47, 1 Mesitylcne, condensation with dichloro methyl methyl ether, 47, 1 Methalljl chloride in alkylation of 2,4-pentanedione with potassium carbonate, 47, 87... 

Malonic acid, amino-, diethyl ester, HYDROCHLORIDE, 40, 24 Malonic acid, bts(hydroxymethyl)-, DIETHYL ETHER, 40, 27 Malonitrile, condensation with tetra-cyanoethylene, 41, 99 2-Mercaptopyrimidine, 43, 6S hydrochloride of, 43, 68 Mercuric oxide in preparation of bromo-cyclopropane, 43, 9 Mesityl isocyanide, 41,103 5-Methallyl-l,2,3,4,5-pentachlorocyclo-pentadiene, 43, 92 Methane, dimesityl-, 43, 57 Methanesiileinyl chloride, 40, 62 Methanesulfonic acid, solvent for making peroxybenzoic acid from benzoic acid, 43, 93... 

C)H7CI03 5538-51-2) see Benorilate Phenprocoumon (2-acetoxybenzoyl)(l-phenylpropyl)malonic acid diethyl ester... 

C3H5S 870-23-5) see Altizide allyl(l-methyl-2-pentynyl)malonic acid diethyl ester (C16H24O4 101448-52-6) see Methohexital 4-allyloxy-3-chlorobenzaldehyde (CigH Cl02, 58236-91-2) see Alclofenac 4-allyloxy-3-chlorobenzyl chloride (C Hi()Cl20 20788-43-6) see Alclofenac 4-allyloxy-3-chlorobenzyl cyanide (C, H C1N0 20788-44-7) see Alclofenac... 

MALONALDEHYDE, NITRO-, SODIUM DERIVATIVE, 32, 95 Malonic acid, 31, 35 33, 20, 62 Malonic acid, ethylidene, diethyl ESTER, 32, 54... 

MaLONIC ACID, ETHYLHYDROXY-, DIETHYL ESTER, BENZOATE, 45, 37... 

Preparation of the intermediate for Allobarbitone (diethyl diallyl malonate). Diethyl malonate is dissolved in anhydrous alcohol and treated with one mole of clean sodium meted per every one mole of the ester. To this solution add one mole of allyl chloride and reflux for about 4 hours. Another equimolar ratio (1 mole of sodium per mole of ester) of sodium is added, followed by the same ratio of allyl chloride (1 mole per 1 mole), and this mixture is boiled for 2 hours. The alcohol is removed by distillation and the ester is extracted with benzene and distilled or evaporated in vacuo, recrystallized with a suitable "dry" solvent, and filtered. Evaporate again to remove traces of solvent. Keep this product, and any other substances that require dry reagents or solvents, stored away from contact with the atmosphere. When evaporating, filter the air coming into the evaporating vessel with a suitable drying agent. Use a little common sense. 

The barbiturates were widely used as sedative-hypnotic drugs. Barbital was introduced as a drug in 1903. The method of synthesis for thousands of its analogs has undergone little change. Urea reacts with various derivatives of malonic acid, usually a diethyl ester of a dialkyl substituted malonic acid. This is a classic example of a nucleophilic acyl substitution. A derivative of ammonia reacts with esters to form an amide, only in this case a cyclization to a strainless six-membered ring results because of the proximity of the bifunctionality. 

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