Sodium acetoacetic ester

Further proof that isoleucine has this constitution was given by Bouveault and Locquin in 1906. They synthesised it from sec. butyl-acetoacetic ester, which they prepared from sec. butyliodide and sodium-acetoacetic ester —... 

Solid sodium acetoacetic ester is first prepared by dissolving 5 gms. of sodium in 40 gms. of alcohol, and after adding an equal volume of dry ether, acetoacetic ester (28 gms.) diluted with its own volume of ether, is gradually added with shaking. 

Dry sodium acetoacetic ester (20 gms.), which is prepared according to the method given under di-acoto-succinic ester, is dissolved in ether, and acetyl-clilorido (12 gms.) is added slowly, A vigorous reaction takes place, which may be completed by warming, after which a little water is added to dissolve sodium chloride, and the ethereal layer separated. After removal of the ether the remaining oil is distillod undor reduced pressure. B.p. at 50 mm. is 122—124°. Yiold, about 20 gins. 

Another interesting synthetic approach which also constitutes a total synthesis was accomplished by Pace (4 ). Sodium acetoacetic ester was oxidized with iodine, the product saponified, and carbon dioxide eliminated to give 2,5-hexanedione. The diketone was reduced to the diol, which was transformed to the dibromide. The hexadiene was formed and converted to the tetrabromide and subsequently to the hexabromide, which upon treatment with alcoholic potassium hydroxide gave DL-mannitol. 

C HgNjOjS. Colourless needles, with iH20. Prepared by reducing diazotized sulphanilic acid with an excess of sodium sulphite. It is a typical hydrazine in its reactions with ketones, and with acetoacetic ester. The latter reaction gives rise to the tartrazine dyestuffs, and is much used commercially. 

The acetoacetic ester condensation (involving the acylation of an ester by an ester) is a special case of a more general reaction term the Claisen condensation. The latter is the condensation between a carboxylic ester and an ester (or ketone or nitrile) containing an a-hydrogen atom in the presence of a base (sodium, sodium alkoxide, sodamide, sodium triphenylmethide, etc.). If R—H is the compound containing the a- or active hydrogen atom, the Claisen condensation may be written ... 

Malonic ester, like acetoacetic ester (Section 111,151), when treated with an equivalent of sodium ethoxide, forms a mono-sodium derivative, which is of great value in synthetical work. The simplest formulation of the reaction is to r rd it as an attack of the basic ethoxide ion on a hydrogen atom in the CH, group the hydrogen atoms in the CHj group are activated by the presence of the two adjacent carbethoxyl groups ... 

Simple esters (e.g., ethyl acetate) undergo the acetoacetic ester condense tion (compare Section 111,151). The effective condensing agent is sodium ethoxide, produced by the action of sodium upon traces of alcohol present in the ester ... 

The formation of acyloins (a-hydroxyketones of the general formula RCH(OH)COR, where R is an aliphatic residue) proceeds best by reaction between finely-divided sodium (2 atoms) and esters of aliphatic acids (1 mol) in anhydrous ether or in anhydrous benzene with exclusion of oxygen salts of enediols are produced, which are converted by hydrolysis into acyloins. The yield of acetoin from ethyl acetate is low (ca. 23 per cent, in ether) owing to the accompanying acetoacetic ester condensation the latter reaction is favoured when the ester is used as the solvent. Ethyl propionate and ethyl ji-butyrate give yields of 52 per cent, of propionoin and 72 per cent, of butyroin respectively in ether. 

On Irealmenl wilh alkoxide bases esters undergo self condensalion lo give a p kelo ester and an alcohol Elhyl acelale for example undergoes a Claisen condensalion on Ireal menl wilh sodium elhoxide lo give a p kelo ester known by ils common name ethyl ace toacetate (also called acetoacetic ester)... 

Manufacture and Uses. Acetoacetic esters are generally made from diketene and the corresponding alcohol as a solvent ia the presence of a catalyst. In the case of Hquid alcohols, manufacturiag is carried out by continuous reaction ia a tubular reactor with carefully adjusted feeds of diketene, alcohol, and catalyst, or alcohol—catalyst blend followed by continuous purification (Fig. 3). For soHd alcohols, an iaert solvent is used. Catalysts used iaclude strong acids, tertiary amines, salts such as sodium acetate [127-09-3], organophosphoms compounds, and organometaHic compounds (5). 

Methylsuccinic acid has been prepared by the pyrolysis of tartaric acid from 1,2-dibromopropane or allyl halides by the action of potassium cyanide followed by hydrolysis by reduction of itaconic, citraconic, and mesaconic acids by hydrolysis of ketovalerolactonecarboxylic acid by decarboxylation of 1,1,2-propane tricarboxylic acid by oxidation of /3-methylcyclo-hexanone by fusion of gamboge with alkali by hydrog. nation and condensation of sodium lactate over nickel oxide from acetoacetic ester by successive alkylation with a methyl halide and a monohaloacetic ester by hydrolysis of oi-methyl-o -oxalosuccinic ester or a-methyl-a -acetosuccinic ester by action of hot, concentrated potassium hydroxide upon methyl-succinaldehyde dioxime from the ammonium salt of a-methyl-butyric acid by oxidation with. hydrogen peroxide from /9-methyllevulinic acid by oxidation with dilute nitric acid or hypobromite from /J-methyladipic acid and from the decomposition products of glyceric acid and pyruvic acid. The method described above is a modification of that of Higginbotham and Lapworth. ... 

The formation of ethyl acetoacetate occurs, according- to Claisen, in four steps. The presence of a small quantity of alcohol gives lise to sodium ethylate, which forms an additive compound with ethyl acetate. The latter unites with a second molecule of ethyl acetate yielding the sodium salt of ethyl acetoacetate, and splitting off alcohol, which reacts with fresh metallic sodium. The sodium salt on acidifying passes into the tautomeric (ketonic) form of acetoacetic ester. 

Ethylmalonic Acid.—Like acetoacetic ester (see p. 83), diethylmalonate contains the gioup CO.CHj.CO. By the action of sodium or sodium alroholate, the hydrogen atoms of the methylene group are successively replaceable by sodium. The sodium atoms are in turn replaceable by alkyl or acyl groups. Thus, in the present preparation, ethyl malonic ester is obtained by the action of ethyl iodide on the monosodium compound. If this substance be treated with a second molecule of sodium alcoholate and a second molecule of alkyl iodide, a second radical would be in roduced, and a compound formed of the general formula... 

Both the malonic ester synthesis and the acetoacetic ester synthesis are easy to cany out because they involve unusually acidic dicarbonyi compounds. As a result, relatively mild bases such as sodium ethoxide in ethanol as solvent can be used to prepare the necessary enolate ions. Alternatively, however, it s also possible in many cases to directly alkylate the a position of monocarbonyl compounds. A strong, stericaliy hindered base such as LDA is needed so that complete conversion to the enolate ion takes place rather than a nucleophilic addition, and a nonprotic solvent must be used. 

Whether a carbon-metal bond is ionic or polar-covalent is determined chiefly by the electronegativity of the metal and the structure of the organic part of the molecule. Ionic bonds become more likely as the negative charge on the metalbearing carbon is decreased by resonance or field effects. Thus the sodium salt of acetoacetic ester has a more ionic carbon-sodium bond than methylsodium. 

C2HjNa02, 127-09-3) see a-Acetyldigoxin Dextrothyroxine Fluazacort Fluprednidene acetate Pioglitazone Pyrrocaine sodium acetoacetic acid ethyl ester (C HyNaO, 19232-39-4) see Pentoxifylline sodium acetylide (Na(C2H))... 

Esters of dicarboxylic acids having hydrogen on the 8 or e carbon atcans undergo intramolecular cyclisation when heated with sodium or with sodium ethoxide. This cyclisation is known as the Dieckmaim reaction. It is essentially an application of the Claiseu (or acetoacetic ester) condensation to the formation of a ring system the condensation occurs internally to produce s... 

The reaction mixture is cooled, 250 cc. of water is added, and mixture is made acid to litmus by addition of a cooled solu-koa of 100 g. of concentrated sulfuric acid in 200 cc. of water. Chipped ice is added if necessary to keep the mixture cool. The ui >er ester layer is separated, and the aqueous layer is extracted w% 200 cc. of ether. The combined ether and ester layers are ken with 350 cc. of a saturated sodium bicarbonate solution yr til no more carbon dioxide is evolved, and then the organic layer 1S fashed with 200 cc. of water. The water layer is combined with sodium bicarbonate solution and extracted with 400 cc. of e er. The combined ether and ester layers are dried over sodium Sl)lfate. The ether is removed by distillation on the steam bath, aiM the excess ethyl benzoate and acetoacetic ester (Note 3) are t removed by distillation under reduced pressure through a l tm. fractionating column. Finally, the ethyl benzoylacetate is tilled (Note 3) at 101-106°/1 mm. (130-135°/3 mm.). The y ld of ester boiling over a 5° range is 190-210 g. (50-55 per cent theoretical amount based on the ethyl acetoacetate). 

Still another possibility in the base-catalyzed reactions of carbonyl compounds is alkylation or similar reaction at the oxygen atom. This is the predominant reaction of phenoxide ion, of course, but for enolates with less resonance stabilization it is exceptional and requires special conditions. Even phenolates react at carbon when the reagent is carbon dioxide, but this may be due merely to the instability of the alternative carbonic half ester. The association of enolate ions with a proton is evidently not very different from the association with metallic cations. Although the equilibrium mixture is about 92 % ketone, the sodium derivative of acetoacetic ester reacts with acetic acid in cold petroleum ether to give the enol. The Perkin ring closure reaction, which depends on C-alkylation, gives the alternative O-alkylation only when it is applied to the synthesis of a four membered ring ... 

Hydroxymethy lene compounds are O-alkylated by potassium carbonate and an alkyl halide in acetone, but these conditions produce only the usual C-alkylation with /J-diketones or keto esters.423 Nitro-compounds have also been reported to give either O- or C-alkylation.424 While acylation of the sodium derivative of acetoacetic ester normally takes place on carbon, O-acylation is the result in pyridine. 

The esters of nitrous acid are characterised by their high velocities of formation and hydrolysis. They are almost instantaneously decomposed by mineral acids and in the method of preparation given this has been taken into account. The slightest excess of hydrochloric acid must be avoided. Advantage is taken of this property of the alkyl nitrites in all cases where it is desired to liberate nitrous acid in organic solvents (in which metallic nitrites are insoluble). Examples addition of N203 to olefines, preparation of solid diazonium salts (p. 286), production of isonitroso-derivatives from ketones by the action of HN02. This synthesis is often also carried out in the manner of the acetoacetic ester synthesis, with ketone, alkyl nitrite, and sodium ethylate the sodium salt of the isonitrosoketone is formed (cf. in this connexion p. 259) ... 

The reason why the acyloin synthesis is especially characteristic of aromatic aldehydes, depends on the circumstance that in the aromatic series the tertiary carbon atom in the ring does not allow of the aldol condensation, a reaction for which conditions are otherwise much more favourable. The simplest example of the acyloin condensation, moreover, was already encountered in the case of formaldehyde (p. 218) glycollic aldehyde is the simplest acyloin. Acyloin compounds are also produced, in the aliphatic series, by the action of sodium or potassium on esters, and hence are also formed as by-products in the acetoacetic ester synthesis (Bouveault, Scheibler). 

Metamizole sodium Methamizole sodium, l-phenyl-2,3-dimethyl-4-methylaminopyra-zolone-5-A -sodium methansulfonate (3.2.16), is synthesized in a multi-stage synthesis from acetoacetic ester and phenylhydrazine. Their reaction leads to the formation of 1-phenyl-3-methylpyrazolone-5 (3.2.9). Methylation of this product with methyl iodide gives 1-phenyl-... 

Isodehydroacetic acid has been prepared by the action of sulfuric acid on acetoacetic ester 3 4 The ethyl ester has been prepared by the action of dry hydrogen chloride on acetoacetic ester 6 6 and by the sodium-catalyzed condensation of ethyl /3-chloroisocrotonate with ethyl acetoacetate3 The methyl ester of isodehydroacetic acid has been prepared by the thermal rearrangement of pyrazolines 7... 

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