Synthesis from Acetoacetate

The most recent work in this field is that of Nagai (1951), who examined chromatographically the nature of the substances in plant cells 

Reiner s (1952) conclusions on the validity of the method as applied to animal tissues are very similar to those of Nagai, in that whereas the specificity of the reaction was found to be reasonably good, no deductions based on the localized deposition of silver particles in the cells could be made owing to diffusion phenomena. 

Histochemical studies indicate that ascorbic acid is highly concentrated in the Golgi apparatus, and mitochondrial elements in the animal cell (Bourne, 1935) and these show changes in scorbutic animals which are rectified when ascorbic acid is supplied (Miwa, 1939). The most definite evidence we have as yet of the site of formation within the cell comes, as we have already seen, from the work of Mapson et al. (1954), who have shown that at least one stage in the synthesis is catalyzed by enzymes localized within the mitochondria. These observations have now been extended to animals, where very similar results have been obtained with mitochondria from liver tissue (Isherwood et al., 1954). 

Dependence op Biosynthesis on External Factors in Plants 

Our knowledge of the factors which affect the biosynthesis of the vitamin has been obtained largely from studies of plants. The reason for this is not diflicult to understand their capacity for synthesis is greater than animals, and the influence of external factors such as light and anaerobic conditions can be more closely determined with plants than with animals. 

---

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-... 

Nifedipine 218 and other related 1,4-dihydropyridines are important as antihypertensive agents (Ca antagonists). They are prepared by a classical Hantzsch synthesis from acetoacetic ester, arylaldehyde and NH3 [72]. Sulfapyridine 219 was one of the first sulfonamide antibacterial agents to be used. Cerivastatin (Lipobay) 220, a powerful HMG-CoA reductase inhibitor, is applied for treatment of primary hypercholesteremia types Ila and b. 

The preparation of 2 4-dimethyl-3 5-dicarbethoxypyrrole (II) is an example of the Knorr synthesis of pyrrole derivatives, involving the reaction of an -aminoketone (or a derivative thereof) with a reactive methylene ketone (or a derivative thereof). The stages In the present synthesis from ethyl acetoacetate (I) may be represented as follows ... 

Related and equally important reactions are the acetoacetic ester synthesis and the eyanoaeetie ester synthesis Here too the initial substituted product can be hydrolyzed and decarboxylated, to yield a ketone 11 (i.e. a substituted acetone) from acetoacetic ester 10, and a substituted acetonitrile 14 from eyanoaeetie ester 13 respectively. Furthermore a substituted acetoacetic ester can be cleaved into a substituted acetic ester 12 and acetate by treatment with strong alkali ... 

Nifedipin Nifedipine, dimethyl ether l,4-dihydro-2,6-dimethyl-4-(2 -nitrophenyl)-3,5-piridindicarboxylic acid (19.3.16), is synthesized by a Hantsch synthesis from two molecules of a j3-dicarbonyl compound—methyl acetoacetate, using as the aldehyde component—2-nitrobenzaldehyde and ammonia. The sequence of the intermediate stages of synthesis has not been completely established [20-23]. 

Some free acetoacetate is formed by direct hydrolysis of acetoacetyl-CoA. In rats, 11% of the hydroxybutyrate that is excreted in the urine comes from acetoacetate generated in this way.64 However, most acetoacetate arises in the liver indirectly in a two-step process (Eq. 17-5) that is closely related to the synthesis... 

Acetic acid, (3,5,6-trichloro-2-pyridinyloxy)-as herbicide, 2, 513 Acetic formic anhydride chromone synthesis from, 3, 820 Acetoacetic acid ethyl ester... 

A specific transport protein, the carnitine-acylcarnitine translocase, moves the fatty acylcarnitine into the mitochondrial matrix while returning carnitine from the matrix to the cytoplasm. Once inside the mitochondria, another enzyme, carnitine palmitoyltransferase II (CPT II), located on the matrix side of the mitochondrial inner membrane, catalyzes the reconversion of fatty acylcarnitine to fatty acyl-CoA. Intramitochondrial fatty acyl-CoA then undergoes (3-oxidation to generate acetyl-CoA.Acetyl-CoA can enter the Kreb s cycle for complete oxidation or, in the liver, be used for the synthesis of acetoacetate and P-hydroxybutyrate (ketone bodies). 

Problem 17.15 Devise a synthesis of C6H5CH2CH2COCH2COOH from acetoacetic ester. -4... 

As in the malonic ester synthesis, you should identify the structural fragments of the target compound. The acetoacetic ester synthesis converts an alkyl halide to a methyl ketone ("substituted acetone"). The methyl ketone component comes from acetoacetic ester the other component comes from a halide. 

Saponification of an ester is the last step in an elegant synthesis of highly branched trialkylacetic acids from acetoacetic ester. An a,a-dialkylacetoacetate is reduced to the /3-hydroxy ester, which, in turn, is dehydrated to a /3, y-olefinic ester. Catalytic hydrogenation followed by saponification then gives the desired product. ... 

Problem 26.8 Outline the synthesis of the following compounds from acetoacetic ester, benzene, and alcohols of four carbons or less ... 

Outline the synthesis of each of the following from acetoacetic ester and any... 

When treated with concentrated alkali, acetoacetic ester is converted into two moles of sodium acetate, (a) Outline all steps in a likely mechanism for this reaction. (Hint See Sec. 21.11 and Problem 5.8, p. 170.) (b) Substituted acetoacetic esters also undergo this reaction. Outline the steps in a general synthetic route from acetoacetic ester to carboxylic acids, (c) Outline the steps in the synthesis of 2-hexanone via acetoacetic ester. What acids will be formed as by-products Outline a procedure for purification of the desired ketone. (Remember that the alkylation is carried out in alcohol that NaBr is formed that aqueous base is used for hydrolysis and that ethyl alcohol is a product of the hydrolysis.)... 

Arndt, F., Eistert, B., Scholz, H., Aron, E. Synthesis of dehydracetic acid from acetoacetic ester. Ber. 1936, 69B, 2373-2380. 

Conrad, M., Limpach, L. The synthesis of quinoline derivatives from acetoacetic ester. Ber. 1887, 20, 944-948. 

Hantzsch, A. Synthesis of pyridine derivatives from acetoacetic ester and aldehydeammoniak. Liebigs Ann. Chem. 1882, 215,1-82. 

Examples of pyridazine synthesis from azines involve reaction between tetrafluoroformaldazine and perfluorosuccinyl fluoride in the presence of cesium fluoride to give a perfluoropyridazine, or via ketazine anions, as for acetophenone azine [Eq. (3)]. The azine from benzyl monohydrazone and ethyl acetoacetate or benzoylacetate is cyclized under basic conditions into the pyridazine 17. ... 

Starting with a preformed A-ring, in the form of phthalide (162), Harris and cowotkers assembled the anthracene derivative (164) as shown in Scheme 8. The intermediate tetraketo diester (163) closes spontaneously under the conditions of its synthesis from (162) and the dianion of r-butyl acetoacetate. 

---