Glutarimides

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. 

By partial reduction of glutarimide 63 with Vitride in toluene at -78 °C followed by acid treatment (HCl) afforded pyrido[2,l-6][l,3]benzoxaine 33 (R = H) (01OL193). 

The glutarimide best known to the lay public, thalidomide (40), owes its reputation not to efficacy, but to the wholly unanticipated and tragic teratogenic effects elicited by this compound. It might be noted that the very efficacy and lack of the usual barbiturate side effects shown by this drug led to its prescription as a hypnotic for expectant mothers. Condensation of the phthalimide of glutamic acid (39) with ammonia at elevated... 

Chemical Name 3-(4-Aminophenyl)-3-ethyl-2,6-piperidinedione Common Name 0 -(p-aminophenyl)-a-ethyl-glutarimide Structural Formula ... 

The 0 -(p-nltrophenyl)-a-ethyl-glutarimide starting material can be prepared as follows 217 g of 0 -phenyl-a-ethyl-glutarimlde are dissolved in 800 g of concentrated sulfuric acid with subsequent cooling to about -10°C and nitration Is carried out at -10°to -f10°C by slow addition of a mixed acid consisting of 110 g of concentrated suifuric acid and 110 g of 63% nitric acid. The nitration solution is stirred into ice, the separated nitro compound taken up in methylene or ethylene chloride, the solution washed with water and sodium carbonate solution until... 

Reduction of glutarimides with sodium borohydride40 or lithium aluminum hydride41 seems to occur preferentially at the less hindered carbonyl group. 

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... 

Obrig, T. G., Culp, W. J., McKeehan, W. L., and Hardesty, B. (1971). The mechanism by which cycloheximide and related glutarimide antibiotics inhibit peptide synthesis on reticulocyte ribosomes. J. Biol. Chem. 246, 174-181. 

In a 500-ml. three-necked flask fitted with a sealed mechanical stirrer and a reflux condenser are placed 86 g. (1 mole) of 7-butyrolactone (Note 1) and 72 g. (1.1 moles) of potassium cyanide (Note 2). As the contents of the flask are stirred, the mixture is heated in an oil bath for 2 hours at a temperature of 190-195° (Note 3). There is an initial vigorous reaction which soon subsides. After the completion of the heating period the mixture is cooled to about 100°, and the potassium salt of the cyano acid is dissolved in about 200 ml. of hot water. The warm solution is cautiously acidified to Congo Red by the addition of about 90 ml. of concentrated hydrochloric acid. The resultant solution, which contains glutaric acid monoamide and potassium chloride, is used to prepare glutaric acid or glutarimide. 

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... 

Thalidomide (USA) a- (N-phthalimido) glutarimide TNF expression inhibitor Erythema nodosum leprosum, cGVHD... 

Considering now glutarimide derivatives, we find that 2-phenylglutari-mide (4.196, R=H) was not a substrate for the partially purified rat liver DHPase, in contrast to glutarimide itself [114][123], Thus, here, the introduction of the Ph group had the opposite effect than in succinimide derivatives. Similarly, no ring-opened metabolite of glutethimide (4.196, R=Et) was found either in vitro or in vivo [124],... 

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. 

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