Glutarimide, hydrolysis

That the methyl group in the less substituted isomer of the enamine (20) is axial was borne out by the work of Johnson et al. (18) in the total synthesis of the glutarimide antibiotic //-dehydrocycloheximide (24). The acylation of the morpholine enamine of 2,4-dimethylcyclohexanone (25) with 3-glutarimidylacetylchloride (26), followed by the hydrolysis of the intermediate product (27) with an acid buffer, led to the desired product in 35 % yield. The formation of the product in a rather low yield could most probably be ascribed to the relatively low enamine-type aetivity exhibited by the tetrasubstituted isomer, which fails to undergo the acylation reaction, and also because in trisubstituted isomer one of the CHj groups is axial. Since the methyl groups in the product are trans to each other, the allylic methyl group in the less substituted isomer of the enamine should then be in the axial orientation. 

Glutarimides may be regarded as oxidized piperidines, and many drugs containing this moiety are sedatives and anticonvulsants. A spiro derivative, alonimid (105) is such a sedative-hypnotic agent. It can be prepared by K t-butoxide catalyzed biscyano-ethylation of phenylacetonitrile, leading to 101. Alkaline hydrolysis produces tricarboxylic acid 102 which is smoothly Converted to the glutaric acid anhydride (103) with acetic anhydride. Friedel-Crafts... 

Glutarimide has been prepared from glutaric acid and sulfamide 3 or formamide,4 by distillation of ammonium glutarate,6 by hydrolysis of pentanedinitrile with acetic acid,6 and by oxidation of piperidine with hydrogen peroxide.7... 

Although slow hydrolysis of the glutarimide ring occurs in buspirone (4.197), ring opening proceeds by intramolecular catalysis, as discussed in Chapt. 11. 

One should not conclude from the above that the glutarimide ring is always resistant to hydrolysis. Indeed, its hydrolysis is a major metabolic pathway for the thalidomide analogue EM12 (4.198). After administration of EM 12 to marmoset monkeys, two products of hydrolysis, 4.199 and 4.200, were found in urine. The concentrations of the two metabolites were similar after administration of the racemate. In contrast, regioselectivity (i.e.. different ratios of the two metabolites) was seen after separate administration of the enantiomers [125],... 

We will now consider supidimide (5.66) as an example of a molecule containing a six-membered lactam ring. The piperidin-2-one ring of this potential sedative underwent slow chemical hydrolysis in buffer solution to yield 5.67, but was resistant to metabolic hydrolysis. The other amide bond was stable [175], Supidimide was primarily metabolized by oxidation of the pi-peridin-2-one ring to yield a glutarimide ring, which then was hydrolyzed as described in Sect. 4.4. 

Acrylamide polymers in aqueous solution undergo thermal hydrolysis and cyclic imide formation. Acrylate, acrylamide and cyclic imide functional groups were detected when a poly(acrylamide) is heated at 150°C in water. The formation of intramolecular imide has been reported in literature. Moradi-Araghi, Hsieh and Westerman reported the formation of cyclic imide in acid, neutral and slightly basic media at 90° C.7 In acidic media, imide formation is favored. In neutral and basic media, both hydrolysis to acrylate and imide formation do occur, but hydrolysis is the dominant reaction. We speculate the high conversion of amine to amide is the result of transamidation, amidation and the nucleophilic addition of the amine to the glutarimide intermediate (Reaction 1). 

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]. 

Benzoxazocinones 129a-c could be converted by acid hydrolysis into glutarimide derivatives 130a-c. Instead, in anhydrous acid medium, such as />-TsOH or TFA in anhydrous MeCN, 129a afforded coumarin 131a from which it was synthesized, demonstrating the full reversibility of the synthetic process (see Scheme 57, Section 14.05.3.7.7) (Scheme 23) <2004SL1584>. 

Hydrolysis, of 2-chloro-l,l,2-trifluoro-ethyl ethyl ether, 34, 49 of a,o -dicyano-/3-ethyl-3-methyl-glutarimide, 36, 29 of 3,4-dihydro-2-methoxy-4-methyl-2H-pyran, 34, 71 of dihydropyran, 30, 48 of ethyl 3-benzyl-2-cyano-3-methyl-pentanoate, 36, 8... 

Just as a lactam can be opened to give an amino acid, an imide gives a similar reaction. A simple example is the hydrolysis of glutarimide, in this case prepared from furfural in four steps, to 5-amino-4-oxo-pentanoic acid (5-aminolevulinic acid, 2.81). This latter compound showed relatively high herbicidal activity. ... 

Partial hydrolysis-cyclization of di[ C]nitriles in contrast produces dilabeled amine heterocycles. [2,6- C2]Glutarimides are the most common products because of their utility as intermediates to pyridines they have been prepared by several different methods in yields of up to... 

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