Imides, acid/base hydrolysis

Acid/base stress testing is performed to force the degradation of a drug substance to its primary degradation products by exposure to acidic and basic conditions over time. Functional groups likely to introduce acid/base hydrolysis are amides (lactams), esters (lactones), carbamates, imides, imines, alcohols (epimerization for chiral centers), and aryl amines. 

Base-catalysed hydrolysis. The hydroxide ion attacks the nitrile carhon, followed hy protonation on the unstable nitrogen anion to generate an imidic acid. The imidic acid tautomerizes to the more stable amide via deprotonation on oxygen and protonation on nitrogen. The base-catalysed amide is converted to carboxylic acid in several steps as discussed earlier for the hydrolysis of amides. 

Amides are also available from nitriles, which have the same oxidation level. Direct acid or base hydrolysis of a nitrile usually requires fairly severe conditions and often does not stop at the amide stage but goes on the carboxylic acid. Treatment of nitriles with a solution of HC1 in ethanol furnishes an imidate ester which is hydrolyzed in aqueous acid to the amide. Because a nitrile is the starting material, only primary amides can be produced by this process. 

Much of the a-deprotonation chemistry of the amides is mirrored by hindered thioamides, imides, ureas, carbamates and phosphonamides,28 and the important asymmetric versions of these reactions are discussed in chapters 5 and 6. Difficulties removing the heavily substituted groups required for protection of the carbonyl group in these compounds have been overcome in such cases as the urea 75, which is resistant to strong base, but which undergoes acid-catalysed hydrolysis and retro-Michael reaction to reveal the simpler derivative 76.54... 

A15.1.1.9 Imides. Compounds that have two acyl groups bonded to a single nitrogen are known as imides (R—CO—NH—CO—R ). The most common imides are cyclic ones (maleimide). Maleimide will convert to maleic acid under water and acid/base. Another example of imide hydrolysis is pheno-barbital in which phenobarbital (a cyclic imide) is hydrolyzed to form urea and a-ethylbenzeneacetic acid. 

The mechanism of nitrile hydrolysis in both acid and base consists of three parts [1] nucleophilic addition of H2O or OH to form the imidic acid tautomer [2] tautomerization to form the amide, and [3] hydrolysis of the amide to form RCOOH or RCOO. The mechanism is shown for the basic hydrolysis of RCN to RCOO (Mechanism 22.11). 

An acid—base reaction forms a nucleophilic anion that can react with an unhindered alkyl halide— that is, CH3X or RCH2X—in an 5 2 reaction to form a substitution product. This alkylated imide is then hydrolyzed with aqueous base to give a 1° amine and a dicarboxylate. This reaction is similar to the hydrolysis of amides to afford carboxylate anions and amines, as discussed in Section 22.13. The overall result of this two-step sequence is nucleophilic substitution of X by NH2, so the Gabriel synthesis can be used to prepare 1° amines only. 

IR spectroscopy may be used to follow two reactions occurring in polyimides exposed to high temperatures and humidities hydrolysis of the imide linkages and hydrolysis of residual anhydride end groups. The hydrolytic susceptibilities of several polyimides were measured at 90°C/95% R.H. Polymers based on benzophenone tetracarboxylic acid dianhydride (with either oxydianiline or m-phenylene diamine) appeared to undergo rather rapid hydrolysis initially, but the reaction had essentially halted by the time the measured imide content had decreased by 5-6%. Polymers based on 3,3 ,4,4 -biphenyl tetracarboxylic acid dianhydride (with p-phenylene diamine) and pyromellitic dianhydride (with oxydianiline) showed no significant imide hydrolysis. In all the polymers, the anhydride was hydrolyzed quite readily. 

Analysis of the acid catalyzed hydrolysis of PAM is complicated due to the possibility of intra- and inter-molecular Imide formation.(4) Perhaps for this reason, studies of the base catalyzed hydrolysis of PAM are more numerous. These investigations indicate that the base catalyzed hydrolysis of PAM may be influenced by a number of factors Including electrostatic Interactions (2,5), nearest neighbor effects (6), and Imide formation associated with specific polymer chain microstructure(s).(7)... 

Hydrolysis of a cyano group in aqueous base involves initial formation of the anion of an imidic acid, which, after proton transfer from water, undergoes keto-enol tautomerism to give an amide. The amide is then hydrolyzed by aqueous base, as we saw earlier, to the carboxylate anion and ammonia. 

Hydrolysis of a Nitrile (Section 18.4E) Either acid or base is required in an amoimt equivalent to that of the nitrile. In acid, the mechanism involves an initial protonation of the nitrile N atom, followed by attack by water to give an imidic acid that tautomer-izes to give an amide, and the rest proceeds the same as for amide hydrolysis in acid. 

The growing living species 1 can be quenched cleanly with so-diomalonic ester to form the target hetero-telechelic polymers (17). The terminal (head) function X (arising from 1 ) may be acetate or imide that in turn leads to a carboxylic acid or an amine, respectively. Another terminal carries a malonate (from the malonate terminator), which can be converted to a carboxylic acid by hydrolysis/ decarboxylation. One of the advantages of the polymer synthesis via the base-stabilized species is the rather high operational temperature up to +60 °C. 

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

Another competing cyclisation during peptide synthesis is the formation of aspartimides from aspartic acid residues [15]. This problem is common with the aspartic acid-glycine sequence in the peptide backbone and can take place under both acidic and basic conditions (Fig. 9). In the acid-catalysed aspartimide formation, subsequent hydrolysis of the imide-containing peptide leads to a mixture of the desired peptide and a (3-peptide. The side-chain carboxyl group of this (3-peptide will become a part of the new peptide backbone. In the base-catalysed aspartimide formation, the presence of piperidine used during Fmoc group deprotection results in the formation of peptide piperidines. 

Initially, water can cause the hydrolysis of the anhydride or the isocyanate, Scheme 28 (reaction 1 and 2), although the isocyanate hydrolysis has been reported to occur much more rapidly [99]. The hydrolyzed isocyanate (car-bamic acid) may then react further with another isocyanate to yield a urea derivative, see Scheme 28 (reaction 3). Either hydrolysis product, carbamic acid or diacid, can then react with isocyanate to form a mixed carbamic carboxylic anhydride, see Scheme 28 (reactions 4 and 5, respectively). The mixed anhydride is believed to represent the major reaction intermediate in addition to the seven-mem bered cyclic intermediate, which upon heating lose C02 to form the desired imide. The formation of the urea derivative, Scheme 28 (reaction 3), does not constitute a molecular weight limiting side-reaction, since it too has been reported to react with anhydride to form imide [100], These reactions, as a whole, would explain the reported reactivity of isocyanates with diesters of tetracarboxylic acids and with mixtures of anhydride as well as tetracarboxylic acid and tetracarboxylic acid diesters [101, 102]. In these cases, tertiary amines are also utilized to catalyze the reaction. Based on these reports, the overall reaction schematic of diisocyanates with tetracarboxylic acid derivatives can thus be illustrated in an idealized fashion as shown in Scheme 29. 

The white residue is next modified by treatment with a strong base in alcohol. It is known that bases can hydrolyze the imide ring of ULTEM polyetherimide (18). Figure 9 shows that both chemical and physical changes to the residue have occurred following immersion in methanolic potassium hydroxide. XPS results are consistent with imide ring hydrolysis and formation of the potassium salt of a carboxylic acid. 

The enzymes of the nucleic acid metabolism are used for several industrial processes. Related to the nucleobase metabolism is the breakdown of hydantoins. The application of these enzymes on a large scale has recently been reviewed [85]. The first step in the breakdown of hydantoins is the hydrolysis of the imide bond. Most of the hydantoinases that catalyse this step are D-selective and they accept many non-natural substrates [78, 86]. The removal of the carbamoyl group can also be catalysed by an enzyme a carbamoylase. The D-selective carbamoylases show wide substrate specificity [85] and their stereoselectivity helps improving the overall enantioselectivity of the process [34, 78, 85]. Genetic modifications have made them industrially applicable [87]. Fortunately hydantoins racemise readily at pH >8 and additionally several racemases are known that can catalyze this process [85, 88]. This means that the hydrolysis of hydantoins is always a dynamic kinetic resolution with yields of up to 100% (Scheme 6.25). Since most hydantoinases are D-selective the industrial application has so far concentrated on D-amino acids. Since 1995 Kaneka Corporation has produced 2000 tons/year of D-p-hydroxyphenylglycine with a D-hydantoinase, a d-carbamoylase [87] and a base-catalysed racemisation [85, 89]. 

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