Carboxamide group, hydrolysis

Pyridazinecarboxamides are prepared from the corresponding esters or acid chlorides with ammonia or amines or by partial hydrolysis of cyanopyridazines. Pyridazinecarboxamides with a variety of substituents are easily dehydrated to nitriles with phosphorus oxychloride and are converted into the corresponding acids by acid or alkaline hydrolysis. They undergo Hofmann degradation to give the corresponding amines, while in the case of two ortho carboxamide groups pyrimidopyridazines are formed. 

A side chain carboxyl group in perhydropyrido[l,2-a]pyrazines was obtained from an ester group by acidic or alkalic hydrolysis. A side chain carboxyl group was converted into a carboxamide group by the treatment with an amine in the presence of 1-hydroxybenzotriazole (OOJAP(K)OO/ 86659). 

Figure 8.2 Polyacrylamide gel formation and hydrolysis of acrylamide to acrylate. (A) Acrylamide and A,A-methylenebisacrylamide (bis) are copolymerized in a reaction catalyzed by ammonium persulfate [(NH4)2S208] and TEMED. (B) A very short stretch of cross-linked polyacrylamide is represented. Cross-linking between similar structures leads to the formation of ropelike bundles of polyacrylamide that are themselves cross-linked together forming the gel matrix. In the lower portion of (B) is shown how pendant, neutral carboxamide groups can become hydrolyzed to charged carboxyls.

During polymerization, acrylamide and bisacrylamide monomers couple together across their double bonds. Linear chains of polyacrylamide form with bisacrylamide molecules cross-linking adjacent chains. The pendant carboxamide groups (-CO-NH2) from the acrylamide monomer are subject to hydrolysis to carboxyls ( COO ) as gels age.42 Only freshly made gels should be used in most IEF work. 

From 2-aminonicotinamides, the C—N chain in the 3-position of the pyridine originates from a carboxamide group which, in turn, may be obtained by hydrolysis of a nitrile function. Cyclization reactions usually require basic conditions and have been performed with a variety of reagents. 

Ar = Ph, X = CN) with a AcONH4-AcOH reagent was reported to be accompanied by hydrolysis of the 3-CN substituent to a carboxamide group (89JPR971). 

Treatment of 649 with ethanedithiol in the presence of boron trifluoride etherate results in acetal—thioacetal interchange at C-6 and subsequent lactonization of the 4)5-hydroxyl group with the r/-butyl ester, thus furnishing 651 in 83% yield. Reduction of the lactone to a lactol, protection with a MOM group, hydrolysis of the thioacetal, and reduction of the ketone with lithium aluminum hydride gives 653 as a single product. After benzoylation of the alcohol, conversion of the OMOM derivative to carboxamide (OMOM —> OAc CN — CONH2) affords 140 as a 10 1 mixture of isomers. 

Aspartimide, cydization product of asparagine in a peptide chain involving the /S-carboxamide group with release of ammonia. The aspartimide derivative may subsequently undergo hydrolysis to give a mixture of a-aspartyl and /S-aspartyl... 

HCl or 0.25 M acetic acid are sufficient to effect hydrolysis of the peptide bonds on both sides of aspartyl residues. For instance the hexapeptide Val-Leu-Gly-Asp-Phe-Pro yields the tripeptide Val-Leu-Gly, the dipeptide Phe-Pro and free aspartic acid. Release of aspartic acid is usually complete after a day of hydrolysis at 100 °C in 0.25 M AcOH while hydrolytic fission of other peptide bonds is negligible. Asparagine creates a notable exception because the carboxamide group in its side chain is fairly sensitive to acid catalyzed hydrolysis and the free carboxyl group of the gradually formed aspartyl residue provides the neighboring group effect which leads to the excision of aspartic acid from the chain. 

The general approach for carboxyl protection is esterification. The simplest solution, the use of methyl or ethyl esters, is suitable for semipermanent blocking, although the commonly applied process of unmasking, alkaline hydrolysis, is far from unequivocal. It is accompanied by racemization, partial hydrolysis of carboxamide groups in the side chain of asparagine and glutamine residues and by several other side reactions which are initiated by proton abstraction (Cf. Chapter VII). Nevertheless, perhaps because of the attractively simple esterification of amino acids... 

The l-aryl-3-trifluorometylpyrazole-5-carboxamide group is present in many of the orally available blood coagulation factor Xa inhibitors. Pinto and co-workers found in their medicinal chemistry program that a fluorinated pyrazole was an optimal five-membered heterocyclic core. Thus, two members of the 3-trifluoromethylpyrazole-5-carboxamide series were advanced to preclinical development (Fig. 2a) [81]. An additional structural modification, the incorporation of an aminobenzisoxazole moiety at N1 instead of the benzylamine group, led to the discovery of razaxaban (Fig. 2b), a potent, selective, and orally bioavailable inhibitor of factor Xa with in vivo efficacy in antithrombotic models [82], The amide hydrolysis observed in vivo could be modulated by introducing bicyclic core variants at the carboxamide portion, such as l/f-pyrazolo[4,3-rf pyrimidin-7(6//)-oneor 1,4,5,6-tetrahydropyrazolo-[3,4-c]pyridine-7-one [83]. 

The respective amide was prepared from 7-substituted 5-oxo-2,3-dihydro-5//-pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylic acids via acid chlorides with different benzylamines (00M1P3). 6-Carboxamides were N-benzylated, and a side-chain phenolic hydroxy group was O-alkylated. 7-Aryl-5-oxo-2,3-dihydro-5//-pyrido[l, 2,3-r/e]-1,4-benzoxazine-6-carboxylic acid was obtained from the ethyl ester by alkalic hydrolysis. 

On the other hand, the reaction of 3-,sec-aminophenols (71) with phthalic anhydride does not give the corresponding keto acids (72). The keto acids (72) having a secondary amino group at 4-position are prepared by the reaction of 3-sec-aminophenols (71) with phthalimide at 150-220°C in the presence of boric acid, followed by hydrolysis of the intermediate carboxamide with aqueous sodium hydroxide (Eq. 3). 

The carboxyl group of 2-[4-(4-carboxybenzoyl)benzyloxy]-3-methyM77-pyrido[l,2- ]pyrimidin-4-one, prepared by hydrolysis of the methyl ester, was reacted first with (Et02C)20 in DMF at room temperature and then with 4-phenylpiperazine and 4-piperidinopiperidine to give the appropriate amide derivatives <1996EPP733633>. The N-substituted derivatives of 4-oxo-477-pyrido[l,2-tf]pyrimidine-3-carboxamides and -3-acetamides and 1,6-dimethyl-4-oxo-l,6,7,8-tetrahydro-477-pyrido[l,2-tf]pyrimidine-3-carboxamide were prepared by treatment of the appropriate... 

Other transformations of the substituents on the N-l atom were also reported <1997JOC7288> (Scheme 9) hydrolysis of the 5-cyano group of derivative 29 to a carboxamide 30 has also been reported. 

The catalysed two-phase alkylation of carboxamides has the advantages of speed and simplicity over the traditional procedures and provides a valuable route to secondary and tertiary amines by hydrolysis or reduction of the amides, respectively. The procedure appears to be limited, however, to reactions with primary haloalkanes and dialkyl sulphates, as secondary haloalkanes are totally unreactive [6, 7]. The use of iodoalkanes should be avoided, on account of the inhibiting effect of the released iodide ion on the catalyst. Also, the A-alkylation reaction is generally susceptible to steric effects, as seen by the low yields in the A -cthylation of (V-/-butylacetamide and of A-ethylpivalamide [6]. However, the low steric demand of the formyl group permits A,A-dialkylation and it is possible to obtain, after hydrolysis in 60% ethanolic sulphuric acid, the secondary amines having one (or, in some cases, two) bulky substituent(s) [7]. 

Next, in steps 7 and 8, N-l of the purine ring is contributed by aspartate. Aspartate forms an amide with the 4-carboxyl group, and the succinocarboxamide so formed is then cleaved with release of fumarate. Energy for carboxamide formation is provided by ATP hydrolysis to ADP and phosphate. These reactions resemble the conversion of cit-rulline to arginine in the urea cycle (chapter 22) and the conversion of IMP to AMP (see fig. 23.11). 

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