Hydantoin 4-imides

Shol996 Short, K.M., Ching, B.W. and MjalU, A.M.M., The Synthesis of Hydantoin 4-Imides on Solid Support, Tetrahedron Lett., 37 (1996) 7489-7492. 

Normal phase Hydantoins, barbiturates imides, oxazolidinones Hydantoins, imides Imides, hydantoins, amino acids... 

Workers at Ontogen [82,83] reported the use of the OntoBLOCK system which utilizes a Tecan robot. They have implemented this technology for solid-phase synthesis to generate over 50 000 compounds corresponding to libraries of pyrroles, phosphonates, phosphinates, lactams, imidazoles, hydantoin imides and thioimides, oxazoles, and b-lac-tams. These libraries have resulted in potent and selective inhibitors of iNOS, PTPases and cdc25 phosphatase and compounds that reverse the P-glycoprotein (Pgp)-based multiple drug resistance (MDR) phenomenon in cellular assays and in animal models [98],... 

Dhnetnyl.hydantoin.imid-(4) 8 290. 4(bzr. 5)-[B-Amino-a.oxy-6thyl]-imidazol... 

The imide proton N-3—H is more acidic than N-1—H and hence this position is more reactive toward electrophiles in a basic medium. Thus hydantoins can be selectively monoalkylated at N-3 by treatment with alkyl haUdes in the presence of alkoxides (2,4). The mono-A/-substituted derivatives (5) can be alkylated at N-1 under harsher conditions, involving the use of sodium hydride in dimethylform amide (35) to yield derivatives (6). Preparation of N-1 monoalkylated derivatives requires previous protection of the imide nitrogen as an aminomethyl derivative (36). Hydantoins with an increased acidity at N-1—H, such as 5-arylmethylene derivatives, can be easily monoalkylated at N-3, but dialkylation is also possible under mild conditions. 

S2S. Street, H. V., Gas-liquid chromatography of submicrogram amounts of drugs. IV. Identification of barbiturates, hydantoins, amides, imides, carbamates, phenylbutazone, carboxylic acids and hydrazine derivatives by direct derivative fonnation within the gas chromatograph. J. Chromaiogr. 41, 358-366 (1969). 

From the chemical point of view, formally, antiepileptic drugs could be classified as derivatives of hydantoins (phenytoin, mephenytoin, ethotoin), barbiturates (phenobarbital, mephobarbital, and primidone), succinimides (ethosuximide, methosuximide, phensux-imide), benzodiazepines (diazepam, chlorodiazepoxide, clonazepam, lorazepam), oxazo-lidines (trimethadione, paramethadione), and also valproic acid, carbamazepine, and acetazolamide. 

Alkylation of the hydantoin (89-2) from benzaldehyde with ethyl iodide takes place at the imide nitrogen to afford ethitoin (89-3) [93]. In much the same vein, treatment of the hydantoin (89-5) from propiophenone with methyl iodide (89-5) in the presence of a base affords mephenytoin (89-6) [94]. Replacement of the quite acidic imide proton by an aUcyl group is not required for activity the well-known anticonvulsant phenytoin (89-8) consists of simply the hydantoin obtained from benzophenone (89-7) [95] this is often formulated as its sodium salt. 

The application of antibiotics as chiral selectors has resulted in the successful resolution of almost all types of neutral, acidic, and basic racemic molecule. These antibiotics have been used for the enantiomeric resolution of amino acids, their derivatives, peptides, alcohols, and other pharmaceuticals. The selectivities of the most commonly used antibiotic-based (vancomycin, teicoplanin, and ristocetin A) CSPs varied from one racemate to another and are given in Table 1. Vancomycin was used for the chiral resolution of amino acids, amines, amides, imides, cyclic amines, amino alcohols, hydantoins, barbiturates, oxazolidinones, acids, profens, and other pharmaceuticals. Teicoplanin was found to be excellent chiral selector for the enantiomeric resolution of amino acids, amino alcohols, imides, peptides, hydantoins, a-hydroxy and halo acids, and oxazolidinones, whereas ristocetin A is capable of chiral resolution of amino acids, imides, amino... 

Reversed phase Amines, amides, imides, acids, profens a-Hydroxy acids, oxazolidinones, amino acids, peptides a-Hydroxy acids, acids, profens, amino acids, amino esters, hydantoins, peptides... 

The search for other amino acid-based catalysts for asymmetric hydrocyanation identified the imidazolidinedione (hydantoin) 3 [49] and the e-caprolactam 4 [21]. Ten different substituents on the imide nitrogen atom of 3 were examined in the preparation, from 3-phenoxybenzaldehyde, of (S)-2-hydroxy-2-(3-phenoxy-phenyl)acetonitrile, an important building block for optically active pyrethroid insecticides. The N-benzyl imide 3 finally proved best, affording the desired cyanohydrin almost quantitatively, albeit with only 37% enantiomeric excess [49]. Interestingly, the catalyst 3 is active only when dissolved homogeneously in the reaction medium (as opposed to the heterogeneous catalyst 1) [49]. With the lysine derivative 4 the cyanohydrin of cyclohexane carbaldehyde was obtained with an enantiomeric excess of 65% by use of acetone cyanohydrin as the cyanide source [21]. 

Many kinds of enzymes with different substrate specificities are involved in hydantoin hydrolysis. Ogawa et al. [10] found two hydantoin-hydrolyzing enzymes in Blastobacter sp. A17p-4. These enzymes were purified to homogeneity and characterized (Table 1). One hydrolyzed dihydropyrimidines and 5-monosubstituted hydantoins to the corresponding AT-carbamoyl amino acids. Since the hydrolysis of 5-substituted hydantoins by this enzyme was D-stereo-specific, this enzyme was identified as D-hydantoinase, which is identical with dihydropyrimidinase. The other one preferably hydrolyzed cyclic imide compounds such as glutarimide and succinimide more than cyclic ureide compounds such as dihydrouracil and hydantoin. Because there have been no reports on enzymes which show same substrate specificity as this enzyme, it is considered to be a novel enzyme, which should be called imidase [10]. 

Analytical Properties Substrate has 38 chiral centers and 7 aromatic rings surrounding 4 cavities (A, B, C, D), making this the most structurally complex of the macrocyclic glycopeptides substrate has a relative molecular mass of 2066 this phase can be used in normal, reverse, and polar organic phase separations selective for anionic chiral species with polar organic mobile phases, it can be used for a-hydroxy acids, profens, and N-blocked amino acids in normal phase mode, it can be used for imides, hydantoins, and N-blocked amino acids in reverse phase, it can be used for a-hydroxy and halogenated acids, substituted aliphatic acids, profens, N-blocked amino acids, hydantoins, and peptides Reference 47, 48... 

In the second major class of amine derivatives, the amidic nitrogen atom can also be A-arylatcd when the sodium salt of the amides is treated with /wra-tolyllead triacetate 58 in CH2C12-DMF at 60-80 °C under mild conditions113,114 (Equations (91)-(93)). Amides as well as sulfonamides, imides, or hydantoins reacted with aryllead triacetates under copper(ll) catalysis, to afford good to excellent yields of the derived A-arylamidcs. In general, better yields were obtained when the sodium salt of the amide was used. For these amidic substrates, the reactions are... 

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]. 

Sheppeck, J. E., II, Gilmore, J. L., Tebben, A., et al. (2007) Hydantoins, triazolones, and imid-azolones as selective non-hydroxamate inhibitors of tumor necrosis factor-oc converting enzyme (TACE). Bioorganic Medicinal Chemistry Letters, 17, 2769-2774. 

Dimethylol-5,5-dimethylhydantoin (DMDMH) and 3-methylol-2,2,5,5-tetramethylimidazolidinone (MTMIO) were mixed in different ratios in textile finishing systems for cellulose fabrics. The mixtures of 2,2,5,5-tetrame thylimidazolidinone (TMIO) and hydantoin rings on the grafted cellulose provided a combination of imide, amide and amine halamine stmctuies in different ratios after chlorination. These combinations improved both the power and stability of the biocidal properties of the treated cotton and polyester/cotton blend fabrics studied. Repeated laundering tests showed that even a small amount of added amine halamines could substantially reduce the loss of active chlorine and increase the power of the biocidal functions on the fabrics. The results were discussed. 12 refs. 

Hydantoins show two bands in the carbonyl region at about 1720 and 1780 cm-1. However, their interpretation has been the subject of controversy. The low-frequency band has been attributed both to the C-4168 and the C-2 carbonyl group.169 Infrared and Raman spectra have also been interpreted in terms of carbonyl coupling similar to that found in imides.170 Other studies have confirmed this coupling.171... 

Aminoethylations with ethylenimine250 and Michael reactions have also demonstrated a preference for the acidic imide function. Thus the N3—H group adds to acetylene to give JV-3-vinylhydantoins251 and to activated ethylenes, such as acrylonitrile or 4-vinylpyridine, to give N-3-substituted hydantoins.25 252 253 Under some conditions 1,3-disubstituted hydantoins are obtained.251... 

Concerning their structure, cyclic imides are closely related to dihydropyrimidines and hydantoins. The metabolic transformation pathway for cyclic imides in microorganisms (see Fig. 12.4-10) was studied by Ogawa et al. S8i 59 in Blastobacter sp. and... 

In fungicidal compounds of type R—S—CCI3, R is generally an imide, hydantoin, 2,4-oxazolidinedione, aliphatic or aromatic sulfonic acid, aliphatic or... 

Barbiturates, hydantoins, and imides contain functional groups related to amides but tend to be more reactive. Barbituric acids such as barbital, phenobarbital, amobarbital, and metharbital undergo ring-opening hydrolysis, as shown in Scheme 15.80-81 Decomposition products formed from these drug substances are susceptible to further decomposition reactions such as decarboxylation. The hydrolysis rates of these substances depend on the substituents Ri, R2, and R3. For some allylbarbituric acids, the effects of these substituents on hydrolysis rates can be explained in terms of Hammett s o value.82... 

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