Piperidine-3,5-diones

Plata, D.J., Leanna, M.R., and Morton, H.E., The stereospecific preparation of an hydroxyethylene isostere precursor via a novel piperidine-2,5-dione template. Tetrahedron Lett.. 32, 3623, 1991. 

The corresponding cyclization of glutamyl residues is mostly insignificant, but glutarimides (piperidine-2,5-diones) are generated from carboxyl-activated N-acyl-glutamines ... 

Neier and coworkers have shown that piperidine diones (e.g., 105) can be prepared stereoselectively using a cascade Diels-Alder/acylation reaction of ketene acetal 104 <96T(52)11643>. 

The piperidine dione structure can be generated by acylation of Meldrum s acid with N-protected /3-amino acids followed by thermolysis of the resulting N-protected fi-amino-/3-ketoacid (Equation 166 Table 6) <2004JOC130>. 

Table 6 Piperidine dione synthesis from N-protected /3-amino acids (Equation 166)...

Dimethyl-5-methyl-2,4-piperidinedione 2,4-Piperidine-dione, 3,3-diethyl-5-methyl Methyprylon U.S.P., N.F., Methyprylone B.P Nodular (Roche) ... 

R)-3-Eth5i-3(4-pyridyl)piperidine-2,6-dione (197), useful in the treatment of certain breast cancers, is a 20-fold more potent aromatase inhibitor... 

Piperidine-2,6-dione, 3-methyIene-polymers, 1, 285 Piperidine-2,4-diones as sedatives, 1, 165 synthesis... 

Cyano-4,6-dlmethyl-2-pyrldone (7) Pentane 2 4 dione 5 (4 85 g 48 5 mmol), cyanoacetamide 6 (4 S g, S3 mmol) and piperidine (2 mL) in EtOH (SO mL) were heated to reflux for 45 mm The product crystallized on cooling Recrystallizatlon from ElOH gave 5 5 4 g of 7 (63 68%) mp298-300 C... 

The striking effect of the catalyst is exemplified by the reaction of pregna-4, 16-diene-3,20-dione (10) with benzyl mercaptan. In the presence of piperidine only conjugate addition occurs to give (11) whereas with pyridine hydrochloride only the 3-benzyl thioenol ether (12) is formed. In the presence of p-toluenesulphonic acid both reactions take place to yield (13). 

The 3-amino-8-oxo derivative of 1,2,4,5,7-pentaazanaphthalene (475) is known as well as various 3-substituted derivatives of the 6,8-dioxo compound. The 3-methylthio- and 3-ethylthio-6,8-dioxo derivatives and their 7-methyl and 5,7-dimethyl analogs were prepared by ring-closure. 3-Ethylthiopyrimido[4,5-e]-as-triazine-6,8-dione was 3-substituted with alkali 2N, 100°, > 30 min) or acid 2N, 100°, < 2 hr, 70% yield) and with ammonia, aniline, piperidine, or monoalkylamines (in pyridine, 115°, 4 hr, 75-85% yield). ... 

Reaction of tetrahydropyridin-4-one 119 and l,r-carbonyldiimidazole furnished l,3,4,4n,5,6-hexahydropyrido[l,2-c][l,3]oxazine-l,6-dione 120 (99JA2651). Similarly, pyrido[l,2-c][l,3]oxazine-l-one 121 and [1,3] oxazino[4,3-n]isoquinoline-4-one 122 were prepared from the respective 2-(2-hydroxypropyl)piperidine and l-(2-hydroxypropyl)-1,2,3,4-tetrahy-droisoquinoline (99JOC3790). Reaction of a 2 1 diastereomeric mixture of l-(l,2-dihydroxyethyl)-6,7-dihydroxy-l,2,3,4-dihydroisoquinolines 123 and 124 with l,l -carbonyldiimidazole gave a 2.7 1 mixture of 1,9,10-trihy-droxy-l,6,7,ll/)-tetrahydro-2//,4//-[l,3]oxazino[4,3-n]isoquinoline-4-ones 125 and 126, which were separated on preparative TLC plate (99BMC2525). 

Cyclization of l-(A -substituted aminocarbonyl)-3-[(tert-butoxycarbonyl) amino]- and -3- [Ai -(tert-butoxycarbonyl)tryptophyl]amino -2-(ethoxycar-bonylmethyl)piperidines (e.g. 188) on the action of NaH gave 2-substituted 5-(substituted amino)perhydropyrido[l,2-c]pyrimidine-l,3-diones (e.g. 159 and 189) (97JMC3402, 97MIP16, 98MI63, 0UMC2219). Cyclization could be also carried out in the presence of DBU (01JMC2219). 

Treatment of the appropriate pipecolic amide 396 with NEta afforded optically active or racemic perhydropyrido[l,2-a]pyrazine-l,4-dione (397) (97USP5703072). (9a5)-Perhydropyrido[l,2-a]pyrazin-3-one (400) was obtained by cyclization of piperidine 398, and the catalytic hydrogenation of quaternary salt 399 over Pd/C (99H(51)2065). 

CSH4F2 372-18-9) see Fluconazole Risperidone 2,4 -difluorobenzophenone (C13HJF2O 342-25-6) see Flutrimazole 4-(2,4-difluorobenzoyl)piperidine hydrochloride (C12H14CIF2NO 106266-04-0) see Risperidone 6a,9-difIuoro-2-chloro-16(i-methyl-ljp,17-dihydroxy-21-acetoxypregna-1,4-diene-3,20-dione (C24H29CIF2O4 23961-22-0) see Halometasone... 

Allylpiperidines were formed from 3-iodomethylperhydropyrido[l,2-f][l,3]oxazin-l-ones by treatment with Zn in AcOH <2002OL3459>. l-Methyl-2-(2-hydroxyalkyl)piperidines were prepared from 3-substituted perhydropyr-ido[l,2-tf][l,3]oxazin-l-ones with lithium aluminium hydride (LAH) in boiling THF and EtzO <2005T1595>. Reaction of 8-methylperhydropyrido[ 1,2-r [ 1.3 ]oxazine-1,3-dione 103 with PhCH2NH2, then PhCOCl and 4-meth-oxyphenol afforded ring-opened products 104 and 105, respectively (Scheme 8) <2000JA11009>. 

Treatment of tert-butyl (2/. )-2-(2-propcny lidene (piperidine-1-carboxylate with McjSil and PhOH yielded 3-substituted-3,4,7,8-tetrahydro-l//,6//-pyrido[l,2-c][l,3]oxazin-l-ones <2005T1595>. Reaction of l-(benzoxycarbonyl)2-styrylpiperidin-4-one with I2 resulted in the formation of r-3,4a-//-/ra r-4-//-4-iodo-3-phenylperhydropyrido[l,2-d-[l,3]oxazine-l,6-dione <2002JOC1972>. A diastereomeric mixture of 3-iodomethylperhydropyrido[ 1,2 z [ 1,3]oxazin-l-ones (e.g., 178) was obtained by intramolecular iodocarbamation of l-(alkoxycarbonyl)-2-allylpiperidines (e.g., 177) with I2 (Equation 34) <1999JOC8402, 2002OL3459>. 

Mild acidic hydrolysis of amino nitrile 369 gave m-4,9a-/7-rra r-9-7/-9-benzyloxy-4-phenyl-3,4,9,9a-tetrahydro-17/,67/-pyrido[2,l-d[l,4]oxazin-l-one <1996TL4001>. (2A)-2-Cyano-l-[(lR)-2-hydroxy-l-phenylethyl]piperidin-6-one, on standing for 20 days in ethanol saturated with HC1 gas, afforded (4/ ,9aA)-4-phenylperhydropyrido[l,2-4[l,4]oxazine-l,6-dione, which was sometimes accompanied by the unstable (26 )-l-[(l/ )-2-hydroxy-l-phenylethyl]-... 

---