Side-chain carboxylic acid

Like aspirin, both ibuprofen and naproxen are relatively simple aromatic compounds containing a side-chain carboxylic acid group. Ibuprofen, sold... 

Selective hydrolysis of the 3a-acetoxy-group of fully acetylated cholic acid derivatives has been achieved with methanolic HCl. The hydrolysis occurs more rapidly than the methylation of the side-chain carboxylic acid. The 3-monosulphates of cholic, chenodeoxycholic, and deoxycholic acids have been prepared using this selective hydrolysis on the fully acetylated methyl esters. The resultant 3a-hydroxy-compounds were then treated with chlorosulphonic acid and the... 

Side-chain carboxylic acids containing a carboxymethyl group a or y to the ring nitrogen are susceptible to facile decarboxylation (Scheme 75). The process is analogous to that with /3-keto acids and it is often very difficult to isolate the compounds (64CPB588). In consequence, it is usual to isolate them as esters or other suitable derivatives (see example in Scheme 55) (550SC(3)413). 

In this chemistry, pivotal final steps in the sequence are a dianion alkylation of the side-chain carboxylic acid, leading to erythro products only. Second, ozonolysis of this product is followed by silyl migration, hydrolysis to a hydroperoxyaldehyde, and, finally, after acidification, cyclization to product. 

The protected acid is activated as its 2,4,6-trichlorophenyl ester, ready for coupling with the phenylalanine methyl ester in base. Now you see why the benzyl ester was chosen to protect Asp s side-chain carboxylic acid group—hydrogenolysis can be used to cleave both the Cbz-group and the benzyl ester at the same time. 

Pyridazine side chain carboxylic acids are most conveniently prepared from open-chain compounds, as for example (6-oxo-l,6-dihydro-4-pyridazinyl)acetic or j8-(6-oxo-l,6-dihydro-3-pyrida-zinyl)propionic acids and derivatives. 

On further oxidation to the final product all the carbon groups of the side chain are completely oxidized and the products are as above, the dimethyl benzenes and toluic acids yielding di-carhoxyl ring acids while ethyl benzene and phenyl acetic acid yield the mono-carboxyl ring acid. This realtionship shows clearly the difference in character between a ring carboxyl acid and an isomeric side-chain carboxyl acid. Because of its isomerism with toluic acid phenyl acetic acid is also known as alpha-toluic acid, a name that does not seem advisable. While phenyl acetic acid is not of especial importance, the other side-chain carboxyl acids which we shall mention are of considerable importance. 

The next higher homologous side-chain carboxyl acid is the one in which the side chain has three carbon groups, CeHs—CH2—CH2— COOH. It is, therefore, beta-phenyl propionic acid or i-carboxy 2-phenyl ethane. It is commonly known as hydrocinnamic acid because of its relation to cinnamic acid as the hydrogenated or reduction product. In the aliphatic series we have two acids, one, propanoic acid or propionic acid, the other propenoic acid or acrylic acid. They are related to each other as corresponding saturated and unsaturated compounds (p. 172). The latter, acrylic acid, yields propionic acid on reduction by the addition of two hydrogen atoms and the conversion of the unsaturated chain into a saturated one. 

Amines are known to coordinate to various metal ions and this has been exploited for their temporary protection, e.g. as zinc and copper(II) chelates.For the selective functionalization of the e-amino group of lysine, the phenolic hydroxy group of tyrosine or the side chain carboxylic acids in aspartic and glutamic acid, the a-amino and the a-carboxy groups are protected as copper chelates. After the desired... 

T Kanazu, T Yamaguchi. Comparison of in vitro carnitine and glycine conjugation with branched-side chain and cyclic side chain carboxylic acids in rats. Drug Metab Dispos 25(2) 149—153, 1997. 

It is now clearly established that the linear NP isomer 4-n-NP can be further oxidized into the corresponding nine-carbon carboxylic acid (Fig. 2 structure X). The glucuronide conjugate of this metabolite has been characterized in mosquitofish bile74. This biotransformation is a key-point in the metabolism of linear side-chain APs. Indeed, from this point, linear APs such as 4-re-NP enter the /3-oxidation metabolic pathway in which each loop results in the loss of two carbon atoms, thereby producing 7-, 5-, 3- and ultimately 1-carbon side-chain carboxylic acid metabolites (Fig. 2 ... 

Cyclization of a sulphonamide and a side-chain carboxylic acid is readily effected by hot PPA when the carboxyl group is replaced by a nitrile, heating with sulphuric acid has a similar effect, but the carbonyl group is replaced by an imino group. 

An improved variant uses a bromopropionamide for the construction of the side-chain carboxylic acid this amide is simply accessible in two stages from cyclohexanone, salicylamide and bromopropionyl bromide. Then follows a Reformatzky reaction with remarkable diastereoselectivity under formal retention of the absolute configuration. [61] Chromatographic purification is not necessary. 

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