1- piperazine,hydrolysis

A number of diarylmethyl alkylpiperazines, such as, for example lidoflazine, have found use as coronary vasodilators for the treatment of angina. The most recent of these interestingly incorporates a 2,6-dichloroaniline moiety reminiscent of antiarrhythmic agents. Treatment of the piperazine carboxamide 124 with acetone leads to formation of the nitrogen analogue of an acetal, the aminal 125. Alkylation of the remaining secondary nitrogen with chloroamide 126 leads to the intermediate 127. Exposure to aqueous acid leads to hydrolysis of the aminal function... 

The initiating nucleophile in the vast majority of these studies is the hydroxide anion. However, in principle, any nucleophile can add to the keto or formyl group to give rise to an anionic intermediate, which then could act as an intramolecular nucleophile and effect hydrolysis of the ester. Their relative effectiveness will depend on two factors the relative extent of formation and the nucleophilicity of the adduct. The nucleophiles that have been investigated are hydroxide, cyanide, morpholine and piperazine. The only quantitative comparison available is that of hydroxide, morpholine and piperazine, which are effective in the order of ca. 102 10-3 1 (Bender et al., 1965 Dahlgren and Schell, 1967). For morpholine and piperazine this is as expected on the basis of their relative basicities. However, the expected order of increasing formation of the adducts would be cyanide > nitrogen bases > hydroxide (Hine, 1971). At this time, these results cannot be analysed further, but more work on the systems could enable the structural dependence and reactivity to be elucidated. 

Tertiary benzamides whose N-atom is part of a cyclic system can also be hydrolyzed metabolically as shown in the following examples. The hydrolysis of the amide group in 6-[4-(3,4-dimethoxybenzoyl)piperazin-l-yl]-3,4-di-hydro-1 //-quinolin-2-one (OPC-8212, 4.85), an inotropic agent, occurred in rats, mice, dogs, monkeys, and humans [54], After oral administration to rats, both products of hydrolysis, namely 3,4-dimethoxybenzoic acid (veratric acid, 4.86) and piperazine-l//-quinolin-2-one (4.87) were detected in the plasma, urine, and feces. 

Kinetic studies of the unnatural 6-a -epimer of ampicillin, fi-ept-ampicillin (154), have revealed an intramolecular process not undergone by ampicillin (or other natural /3-substituted penicillins) At pH 6-9, intramolecular attack of the jS-lactam carbonyl group by the side-chain amino group of (154) yields a stable piperazine-2,5-dione derivative (155). Theoretical calculations show that the intramolecular aminolysis of 6-epi-ampicillin nucleophilic attack occurs from the a-face of the -lactam ring with an activation energy of 14.4kcalmor In other respects, the hydrolysis of the b-a-epimer is unexceptional. 

PIPERAZINES AND PYRAZINES The classical synthetic method for constructing 2-aminopyrazines is illustrated by the synthesis of ampifzine (117), a CNS stimulant. Condensation of aminomalonamide and glyoxal leads to pyrazine 114. Hydrolysis to the acid and decarboxylation gives 2-hydroxypyrazine (115). Reaction with PCl produces chloride 116, and heating with dimethylamine completes... 

Reacting 3-chloro-4-fluoroaniline and ethyl ethoxymethylenmalonate gives the snbsti-tntion prodnct (33.2.15), which upon heating in diphenyl ester cyclizes into ethyl ester of 6-flnoro-7-chloro-l,4-dihydro-3-quinolin-4-on-carboxylic acid (33.2.16). Direct treatment of the prodnct with ethyl iodide in the presence of triethylamine and snbseqnent hydrolysis with a base gives l-ethyl-6-flnoro-7-chloro-l,4-dihydro-3-qninolin-4-on-carboxylic acid (33.2.17). Reacting this with piperazine gives norfloxacin (33.2.18) [70-75]. 

Treatment of the bislactim ethers with two equivalents of 0.25 N hydrochloric acid at room temperature leads to their hydrolysis to their constituent amino acid esters under these conditions (Scheme 56). The hydrolysis does not proceed via the piperazine-2,5-dione since the products are the esters and not the free amino acids. The rate of hydrolysis depends on the number and nature of the substituents at the 3 and 6 positions (83CJC1397). 

The conditions for the hydrolysis of the final piperazine-2,5-dione have been critically examined. A 1 1 mixture of dioxane and aqueous HC1 (1 or 0.5 M) was found to be the best. Some unusqal amino acids, including those having a basic side chain, have been synthesized by this procedure (86BCJ323 89BCJ2315). 

The lability of peptides and proteins to acidic conditions was first reported in 1920 by Dakin,12031 who found that acid hydrolysis of peptides or proteins that contain consecutive N-alkyl amino acids leads to the formation of piperazine-2,5-diones (DKP) this side reaction lowered their yield during amino acid analysis. For example, the piperazine-2,5-dione c[-Hyp-Pro-] was isolated from the hydrolyzate of gelatine. 

The hydrolysis of amides is not limited to the industrial synthesis of enantio-pure amino acids. Lonza has developed routes towards (S)-pipecolic acid and (R)- and (S)-piperazine-2-carboxylic acid that are based on amidases [93, 94]. 

First of all, the steric hindrance may seriou,sly affect yield and/or stability of the product, when bulky substituents arc bound to the amine rcagent. Second, complications may arise, as we have seen before, with polyfunctional amines, mainly ammonia and primary amines, due to the pos.sibilily that the unrcacted hydrogen atoms of the amine may undergo further reaction with formaldehyde, thus producing undesired by-products. Similarly, the use of secondary bifunctional amines, such as piperazine, always leads to a bis-Mannich base, due to reaction of both amino groups. Attempts to limit the reaction to only one amine function, as well as hydrolysis of the Mannich product obtained from aminomethylation of mono-N-acylpiperazines, invariably gives the di.substituted piperazine 23. ... 

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