Carboxyhc acid activation

The synthetic process to prepare keto amide 5 required couphng the carboxyhc acid 2, Meldrum s acid, and the triazole 4 and consists of three key steps carboxyhc acid activation, reaction of the activated acid with Meldrum s acid, followed by reaction with the amine and decarboxylation. As... 

G. Sekar of the Indian Institute of Technology Madras, in Chennai, established (Tetrahedron Lett. 2008, 49, 2457) a convenient procedure for oxidizing primary alcohols such as 26 to the acid 27. Secondary alcohols were oxidized to ketones. AUyhc and benzylic alcohols could be oxidized in preference to saturated alcohols. Tobin J. Marks ofNorthwestem University devised (Organic Lett. 2008,10, 317) a La catalyst for the oxidative amination of aldehydes. In its present incarnation, excess aldehyde served as the reductant. If a less expensive reductant could be found, this would be a very useful procedure, avoiding the carboxyhc acid activation usually required for amide formation. 

Ketopregnan-21-oic Acids, the 17(3-Carboxy Androstanes, and the D-Homocorticoids. In the course of studies on the metabohsm of fluocoitolone (103) the formation of the water-soluble carboxyhc acid (105, R = H) was reported. As a free 21-hydroxyl is not necessary for antiinflammatory activity, it was concluded that the esters (105, R = alkyl) of the preceding metabohte would possess antiinflammatory activity on topical administration but would be devoid of systemic activity when hydrolysis to the free acid occurs followed by... 

Another series of antiinflammatory carboxyhc acids that ate derived from cortienic acid (107), a minor adrenal metabohte, has been described (104,105). Esterification of both the 17a-hydroxyl group and the carboxyhc acid of (107) were requited to develop a compound of high topical potency with low systemic activity. Peak activity was generally associated with a 17a-propionoxy group and a 17P- uoromethoxy carbonyl (eg, (108)), or 17P-methoxycarbonyl residue. 

As a class of compounds, nitriles have broad commercial utility that includes their use as solvents, feedstocks, pharmaceuticals, catalysts, and pesticides. The versatile reactivity of organonitnles arises both from the reactivity of the C=N bond, and from the abiHty of the cyano substituent to activate adjacent bonds, especially C—H bonds. Nitriles can be used to prepare amines, amides, amidines, carboxyHc acids and esters, aldehydes, ketones, large-ring cycHc ketones, imines, heterocycles, orthoesters, and other compounds. Some of the more common transformations involve hydrolysis or alcoholysis to produce amides, acids and esters, and hydrogenation to produce amines, which are intermediates for the production of polyurethanes and polyamides. An extensive review on hydrogenation of nitriles has been recendy pubHshed (10). 

Because of its volatility, the cobalt catalyst codistills with the product aldehyde necessitating a separate catalyst separation step known as decobalting. This is typically done by contacting the product stream with an aqueous carboxyhc acid, eg, acetic acid, subsequently separating the aqueous cobalt carboxylate, and returning the cobalt to the process as active catalyst precursor (2). Alternatively, the aldehyde product stream may be decobalted by contacting it with aqueous caustic soda which converts the catalyst into the water-soluble Co(CO). This stream is decanted from the product, acidified, and recycled as active HCo(CO)4. 

Polarity Parameter. Despite their appareat simplicity, these parameters, ( ), show a good correlatioa with plasticizer activity for nonpolymeric plasticizers (10). The parameter is defiaed 2ls (j) = [M A j Po)]/1000 where M = molar mass of plasticizer, = number of carboa atoms ia the plasticizer excluding aromatic and carboxyHc acid carbon atoms, and Pg — number of polar (eg, carbonyl) groups present. The 1000 factor is used to produce values of convenient magnitude. Polarity parameters provide useful predictions of the activity of monomeric plasticizers, but are not able to compare activity of plasticizers from different families. 

Nitriles. Nitriles can be prepared by a number of methods, including ( /) the reaction of alkyl haHdes with alkaH metal cyanides, (2) addition of hydrogen cyanide to a carbon—carbon, carbon—oxygen, or carbon—nitrogen multiple bond, (2) reaction of hydrogen cyanide with a carboxyHc acid over a dehydration catalyst, and (4) ammoxidation of hydrocarbons containing an activated methyl group. For reviews on the preparation of nitriles see references 14 and 15. 

Condensation catalysts include both acids and bases, as well as organic compounds of metals. Both tin(II) and tin(IV) complexes with carboxyhc acids ate extremely useful. It has been suggested that the tin catalyst is converted to its active form by partial hydrolysis followed by reaction with the hydrolyzable silane to yield a tin—sdanolate species (eqs. 22 and 23) (193,194). 

In humans, thiamine is both actively and passively absorbed to a limited level in the intestines, is transported as the free vitamin, is then taken up in actively metabolizing tissues, and is converted to the phosphate esters via ubiquitous thiamine kinases. During thiamine deficiency all tissues stores are readily mobilhed. Because depletion of thiamine levels in erythrocytes parallels that of other tissues, erythrocyte thiamine levels ate used to quantitate severity of the deficiency. As deficiency progresses, thiamine becomes indetectable in the urine, the primary excretory route for this vitamin and its metaboHtes. Six major metaboHtes, of more than 20 total, have been characterized from human urine, including thiamine fragments (7,8), and the corresponding carboxyHc acids (1,37,38). 

Penam P-Lactamase Inhibitors. Penam is the trivial name given derivatives of the penicillin nucleus (31) the chemical name of which is 4-thia-l-a2abicyclo[3.2.0]heptane. Table 6 gives activity data for a diverse group of penams. The report that 6-P-bromopeniciU.anic acid [26631-90-3] [2(3)-(2a,5a,6P)]-6-bromo-3,3-dimethyl-7-oxo-4-thia-l-a2abicyclo[3.2.0]heptane-2-carboxyhc acid, (31, R = Br, R =H, R" = R " = CH3) a potent... 

Ca.rboxyhc Acids. Esters are the main products in the reaction of chloroformates with carboxyHc acids. The intermediate mixed carboxyhc—carbonic anhydrides are very active acylating agents (25—27) but these agents may be isolated in cold temperatures for producing useful products (28). 

Polyfunctional 2-hydtoxyalk5iamides can serve as cross-linkers for carboxyHc acid-terrninated polyester or acryHc resins (65). The hydroxyl group is activated by the neighboring amide linkage (66). SoHd grades of hydroxyamides are finding use as cross-linkers for powder coatings (67). 

Cannabinoids are highly lipophilic compounds making bioavailabihty very dependent on the formulation and the mode of administration. Cannabinoid occurrence in the plant is predominantly in the form of the carboxyhc acids, which are pharmacologically totally different and rather unstable, decarboxy-lating over time to their active neutral form. The carboxyhc acids, although not active at the CB receptor, nevertheless add to the overall effect as they possess antibiotic and anti-inflammatory effects. 

Zhu et al. [55] also synthesized a series of ester/amide derivatives of 2,3-dimethoxy-8,9-methylenedioxy-benzo[z]phenanthridine-12-carboxyhc acid (X) and evaluated their topo I-targeting activity as well as cytotoxicity against different cell lines. Topo I cleavage values are given as REC, the relative ef-... 

Figure 15 Conjugation of a carboxylic add and an amine using the carbodiimide method. The carbodiimide activates the carboxyhc acid to speed up the reaction to the amine. Carbodiimides can be used with nonpolar or polar solvents, including water. Undesirable urea complexes may form as by-products. Details of the reaction are given in Table 3...

M. M. Corsi, H. H. Maes, K. Wasserman, A. Fulgenzi, G. Gaja, M. E. Ferrero, Protection by L-2-Oxothiazohdine-4-carboxyhc Acid of Hydrogen Peroxide-Induced CD3 and CD 162 Chain Down-Regulation in Human Peripheral Blood Lymphocytes and Lymphokine-Activated Killer Cells , Biochem. Pharmacol. 1998, 56, 657 - 662. 

Recently, hydroxamic acid derivatives of common NSAIDs (meclofen-amic acid, indomethacin, sulindac, and ibuprofen) were evaluated at Warner-Lambert [293]. The order of 5-LO inhibitory potency (in RBL-1 cells) for these derivatives was CON(Me)OH > CONHOH > CONH(OMe)-> COOH. The CO potency ranking was exactly opposite, although the best 5-LO inhibitors still possessed significant CO activity. Whether the observed oral activity in CPE was due to carboxyhc acid metabolites or to the intrinsic activity of the hydroxamic acids was not clear. The more active 5-LO inhibitors were less ulcerogenic in fasted rats. 

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