Functionalized hydantoins

Ester-functional hydantoin monomers (70) were prepared (Scheme 17) and were readily incorporated into polyesters by reaction with suitable diols (72CR(C)1795>. 

A novel reaction of pyroglutamate (6) and an isocyanate promoted by NaH in THF leads to functionalized hydantoins (7) in good yields. The reaction involves the ring closure of intermediate (8) by a nucleophilic attack on the carbonyl of the ester function followed by expulsion of an alkoxide anion resulting in the formation of the bicyclic intermediate (9). The alkoxide anion in turn can open this bicyclic intermediate with formation of anions (10) and (11) leading to the final racemic hydantoins (7) (Scheme 3).8... 

The addition proceeds most smoothly with highly functionalized (more polar) steroids as seen in examples by Bernstein and others. The polar reaction conditions pose solubility problems for lipophilic androstane, cholestane and pregnane derivatives. Improved yields can be obtained in some cases by using dimethyl sulfoxide or t-butanol " as solvents and by using sodium A-bromobenzenesulfonamide or l,3-dibromo-5,5-dimethyl hydantoin (available from Arapahoe Chemicals) as a source of positive bromine. The addition of bromo acetate and bromo formate to steroid olefins has been studied to a limited extent. ... 

For this solid-phase approach, conventional iPrOCH2-functionalized polystyrene resin (Merrifield linker) was employed. After attachment of the requisite substrate, the resin was pre-swollen in a solution of barium(II) hydroxide in N,N-dimethyl-formamide within an appropriate sealed microwave vial. The vial was heated in the microwave cavity for 5 x 2 min cycles (overall 10 min) with the reaction mixture being allowed to cool to room temperature in between irradiation cycles (Scheme 7.50), leading to comparatively modest isolated yields of hydantoins. 

This subsection examines the hydrolytic stability of cyclic structures containing a ureido link. Schematically, ring closure can be achieved by N-alkylation or by /V-acylation of the second N-atom of the ureido moiety. The former results in the formation of, e.g., hydantoins and dihydropyrimidines. The latter ring closure leads to, e.g., barbituric acids. Taken together, cyclic ureides can also be regarded as ring structures that contain an imido function with an adjacent N-atom. We begin our discussion with the five-membered hydantoins, to continue with six-membered structures, namely dihydropyrimidines, barbituric acids, and xanthines. 

Figure 1. Infrared spectra for a toluene diisocyanate modified hydantoin epoxy/2-ethyl-l,3-hexanediol oligomer showing the OH and NH bands of the oligomer as a function of temperature in uncatalyzed and catalyzed formulations.

Drugs that may affect amiodarone include hydantoins, cholestyramine, fluoroquinolones, rifamycins, ritonavir, and cimetidine. Drugs that may be affected by amiodarone include anticoagulants, beta-blockers, calcium channel blockers, cyclosporine, dextromethorphan, digoxin, disopyramide, fentanyl, flecainide, hydantoins, lidocaine, methotrexate, procainamide, quinidine, and theophylline. Drug/Lab test interactions Amiodarone alters the results of thyroid function tests, causing an increase in serum T4 and serum reverse T3 levels and a decline in... 

Hepatic function impairment Biotransformation of hydantoins occurs in the liver elderly patients or those with impaired liver function or severe illness may show early signs of toxicity. 

The C N functionality of a-aminonitriles may also act as a dehydrating/conden-sating center, as it may formally act as water trap and convert to an amide group [126h, i]. As shown in Scheme 6.30, at ambient temperature neat a-aminonitriles react with C02 to afford unsymmetric disubstituted ureas which, in water and at room temperature, can be converted into N-(3)-substituted hydantoins. 

The quaternization method is also highlighted by the short asymmetric synthesis of cell adhesion molecule BIRT-377 (Scheme 5.24), which is a potent inhibitor of the interaction between intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) [16]. Thus, asymmetricp-bromobenzylation of the alanine derivative 42 (R1 = Me) with (S)-18 under similar phase-transfer conditions as described above gave rise to p-bromobenzylalanine ester 10 in 97% ee (83% yield). A similar asymmetric p-bromobenzylation of alanine ethyl ester 42 (R1 = Me, R= Et) gave the amino ester 47 (R= Et) in 90% ee (86% yield). The amino ester 47 (R = t-Bu or Et) was treated with 3,5-dichlorophenyl isocyanate in the presence of sodium carbonate in dimethylsulfoxide (DMSO) to furnish the hydantoin 48 in 86%... 

Since D-hydantoinase was identified as dihydropyrimidinase, it is proposed that D-amino acid production from DL-5-monosubstituted hydantoins involves the action of the series of enzymes involved in the pyrimidine degradation pathway. Based on this proposal, D-decarbamoylase was thought to be identical with P-ureidopropionase (EC 3.5.1.6) which functions in pyrimidine metabolism. 

Topaquinone (TPQ), the oxidized form of 2,4,5-trihydroxyphenylalanine (TOPA), is the cofactor of copper-containing amine oxidases. The following model compounds have been prepared in order to understand the catalytic function of TPQ the jV-pivaloyl derivative of 6-hydroxydopamine in aqueous acetonitrile [38] topaquinone hydantoin and a series of 2-hydroxy-5-alkyl-l,4-benzoquinones in anhydrous acetonitrile (o- as well as />-quinones) [39] 2-hydroxy-5-methy 1-1,4-benzoquinone in aqueous system [40] and 2,5-dihydroxy-1,4-benzoquinone [41]. Reaction of model compounds with 3-pyrrolines revealed why copper-quinopro-tein amine oxidases cannot oxidize a secondary N [42], The studies clearly showed that certain model compounds do not require the presence of Cu for benzylamine oxidation whereas TPQ does [38,40] the aminotransferase mechanism proceeds via the -quinone form [39] the 470 nm band can be ascribed to a 71-71 transition of TPQ in />-quinonic form with the C-4 hydroxyl ionized but hydrogen bonded to some residue [40] hydrazines attack at the C-5 carbonyl, forming an adduct in the azo form [41], Electrochemical characterization has been carried out for free TPQ [43],... 

Melphalan and the racemic analog have been prepared by two general routes (Scheme I). In Approach (A) the amino acid function is protected, and the nitrogen mustard moiety is prepared by conventional methods from aromatic nitro-derivatives. Thus, the ethyl ester of N-phthaloyl-phenylalanine was nitrated and reduced catalytically to amine I. Compound I was reacted with ethylene oxide to form the corresponding bis(2-hydroxyethyl)amino derivative II, which was then treated with phosphorus oxychloride or thionyl chloride. The blocking groups were removed by acidic hydrolysis. Melphalan was precipitated by addition of sodium acetate and was recrystallized from methanol. No racemization was detected [10,28—30]. The hydrochloride was obtained in pure form from the final hydrolysis mixture by partial neutralization to pH 0.5 [31]. Variants of this approach, used for the preparation of the racemic compound, followed the same route via the a-acylamino-a-p-aminobenzyl malonic ester III [10,28—30,32,33] or the hydantoin IV [12]. 

Noort et al. (53) recently demonstrated that phosgene binds effectively to albumin and hemoglobin upon in vitro exposure of human blood to [14C]phos-gene (53). Upon Pronase digestion of globin, one of the adducts identified was the pentapeptide 0=C-(Val-Leu)-Ser-Phe-Ala, representing amino acids 1-5 of a-globin, with a hydantoin function between the N-terminal valine and leucine. This adduct... 

The formation of 3.83 was highly sensitive to experimental conditions, and the use of previously reported protocols for SP intramolecular cyclizations to hydantoins failed. The most abundant isolated side-product was the acid urea 3.100, derived from basic hydrolysis of the ester function this finding led to the successful validation of an anhydrous cyclative cleavage protocol using five equivalents of potassium r-butox-ide in anhydrous THF at RT under an Ar atmosphere for 1 hr (Fig. 3.38). Compound 3.83 was isolated in a satisfactory overall 20% yield (12 steps). 

Table 18 5-HTia, 5-HT2a and D2 affinities and 5-HTia/5-HT2a functional activities of spiro-hydantoins...

Bucherer-Bergs products were also the starting points for the preparation of potent and selective muscarinic M3 receptor antagonists (Table 20) [83]. Hydantoins of general structure 228 (Scheme 40) participated in Mitsunobu reactions with alcohols to provide derivatives 229, which were reduced with sodium bis (2-methoxyethoxy)aluminum hydride (Red-Al) to afford imidazolidinones 230. Removal of the benzyl group allowed for further functionalization of the secondary amines to yield compounds 231. 

The utility of urca.s and thioureas as substrates for making imidazoles is limited by the fact that the imidazole 2-substituent can only be an oxygen or sulfur function. Synthetic methods involving ureas and thioureas will also be discussed in Section 4.1, but some cyclizations of suitably functionalized species fall under the present heading. Appropriately substituted ureas and thioureas can be made from isocyanates and primary amines [36-38], from isocyanates and hydrazines [39] or thiocyanates and hydrazines [40], from or-aminonitrilcs and carbon dioxide [41] and by heating l,3,4-oxadiazol-2-oncs with amino acids [42]. Some of the substrates prepared in these ways, though, lead ultimately to reduced imidazoles such as hydantoins. Cyclizations arc usually acid catalysed, but they can also be thermal [43]. 

A conceptual alternative way to the activation of the carboxylic acid function is the reaction of carboxylic acids with amino groups activated as isocyanates - and isothiocyanates (equation 16). Preparation of these derivatives is racemization free. The reaction proceeds via mixed acid anhydrides in aromatic hydrocarbon solvents at elevated temperatures, and decarboxylation leads to the V-substituted amide. Pyridine as solvent enhances the conversion rate but increases also the amount of the urea side product via disproportionation. Application to peptide chemistry is limited, because peptide ester fragments tend to form hydantoins. ... 

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