Malonic acid, Methyl

This ester (70 g) and diethyl carbonate (250 mg) were stirred at 90°C to 100°C while a solution of sodium ethoxide [from sodium (7.8 g) and ethanol (1 54 ml)] was added over 1 hr. During addition, ethanol was allowed to distill and after addition distillation was continued until the column heat temperature reached 124°C. After cooling the solution to 90°C, dimethyl sulfate (33 ml) was followed by a further 85 ml of diethyl carbonate. This solution was stirred and refluxed for 1 hr and then, when Ice cool, was diluted with water and acetic acid (10 ml). The malonate was isolated in ether and fractionally distilled to yield a fraction boiling at 148°C to 153°C/0.075 mm, identified as the alpha-methyl malonate. This was hydrolyzed by refluxing for 1 hr at 2.5N sodium hydroxide (350 ml) and alcohol (175 ml), excess alcohol was distilled and the residual suspension of sodium salt was acidified with hydrochloric acid to give a precipitate of the alpha-methyl malonic acid. This was decarboxylated by heating at 180°C to 200°Cfor 30 minutes and recrystallized from petroleum ether (BP 80°C to 100°C) to give 2-(2-fluoro-4-biphenylyl)propionic acid, MP 110°C to 111°C. 

The residual oil was stirred and refluxed with sodium hydroxide (75 ml of 5N), water (45 ml) and 95% ethanol (120 ml). Within a few minutes a sodium salt separated and after 1 hour the solid was collected, washed with ethanol, dissolved in hot water and acidified with dilute hydrochloric acid to give the methyl malonic acid which was collected and dried in vacuo MP 177° to 180°C (dec.). 

Cobalt is present in animals in vitamin B12 (cyanocobalamine) and thus is essential for humans (Thunus and Lejeune 1994). The determination of Co has little significance for the diagnosis of deficiency of cyanocobalamine. Instead, cyanocobalamine itself must be determined in serum. The determination of methyl malonic acid in urine seems more reliable (McCann et al. 1996). 

McCann MT, Thompson MM, Gueron IC et al. (1996) Methyl malonic acid quantification by stable isotope dilution gas chromatography-mass spectrometry from filter paper urine samples. Clin Chem 42 9io-9i4. 

The first successful attempt in asymmetric synthesis was made by Marckwald in 1904 who prepared an active (-) -valeric acid by heating the half brucine salt of ethyl methyl malonic acid at 170°C. 

Hydratropic acid Benzeneacetic acid, a-methyl- Malonic acid Propanedioic acid... 

Urinary methyl malonic acid is an indicator for B12 deficiency. Blood homocysteine levels may also rise with B12 or folate deficiency. 

Synthesis from Ethylene Bromide.—Such an acid is known as a commonly occurring substance in nature and is called succinic acid. It has the composition C4H6O4 and is plainly isomeric with methyl malonic acid. Its constitution as given above is, however, proven by the following syntheses Ethylene bromide, or symmetrical di-brom ethane, which is made by the addition of bromine to ethylene gas, yields by treatment with potassium cyanide a symmetrical di-... 

Thus, according to these two syntheses succinic acid must be symmetrical di-acetic acid. As succinic acid is isomeric with methyl malonic acid the latter is also called iso-succinic acid. 

Malonic acid Mono-methyl malonic acid Iso-succinic acid 1 COOH Sucdnic acid... 

FIGURE 5.2 Four organic molecules containing enantiotopic groups ot atoms, (a) isopropyl-cyclohexane (b) 1,3-dimethyl-cydohexane (c) butanone (d) 2-methyl malonic acid. 

A less familiar ring system, but one that was part of a molecule selected for advanced testing, was the 5-methyl-6-oxo-4-(trifluoromethyl)-l-(6H)-pyridazinyl ring system of flufenpyr-ethyl (43). The pyridazinyl heterocycle can be prepared from the reaction of 4-chloro-2-fluoro-5-hydroxyphenyl hydrazine (48) and 1,1-dibromo-3,3,3-trifluoroacetone (49) to give the corresponding hydrazone 50, which when reacted with methyl malonic acid (51), in the presence of a base, provides the intermediate 52. Acid-catalyzed ring closure of 52, followed by 0-alkylation of 53 with ethyl chloroacetate, results in the synthesis of flufenpyr-ethyl (43) [73] (Scheme 3.2). 

HYDROXY-13E-LABDEN-15-YL-METHYL MALONIC ACID (DIESTER)... 

Degradation of the pyrimidines follows route A of Fig. 211 in most organisms. The final products are carbamic acid, which spontaneously hydrolyses to CO2 and NHg, / -alanine (D 16) and jS-aminoisobutyric acid. In some bacteria, however, a second pathway, route B, exists which yields urea and malonic/methyl-malonic acids as the degradation products. 

Methods to assess activity of vitamin B12. These include macrocytic anaemia improvements, homocysteine (Hey) reduction and methyl malonic acid (MMA) reduction. 

Methyl malonic acid (MMA) reduction. Because the bioehemieal pathway that reduees MMA levels in the blood uses only vitamin B12, lowering MMA levels is a test speeific for vitamin B12 activity. Although it is not known for certain, it is likely that this biochemical pathway is an integral part of the function of vitamin B12 in nerve tissue. Thus, if food lowers MMA levels, it can be assumed to provide full vitamin B12 activity. Similarly, the bioavailability of vitamin B12 in lyophilized purple liver was assessed by MMA exeretion to find total vitamin B12 and vitamin B12 analogue eontents in the liver. 

The first discussions concerning the conditions for aeating optically active compounds in the laboratory may be traced to Pasteur and Le Bel. The first mention of the expression "asymmetric synthesis" can be found in the work of E. Fischer in 1894 concerning his stereochemical studies on sugars. He observed the formation of unequal amounts of cyanohydrins in the Kiliani reaction applied to aldehydic sugars. In 1904, Marckwald reported an asymmetric synthesis of 2-methyl-butanoic acid by decarboxylation of 2-ethyl 2-methyl-malonic acid in the presence of an alkaloid. The importance and the mechanism of this reaction were later the subject of much debate. However, this paper remains significant because Marckwald defined asymmetric synthesis, as follows "It is a reaction giving optically active products from symmetrical... 

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