Barbitursäurederivate, 30. Mitt. Synthese racem. und optisch aktiver basisch substituierter Barbitursäuren

Abstract

Durch Kondensation von monoalkylierten Malonestern mit N-monosubstituierten Harnstoffen wurden die 5-monoalkylierten Barbitursauren 1 erhalten, die zu den 5-Brombarbitursauren 2 umgesetzt wurden. Aus 2 wurden durch nucleophile Substitution mit Stickstoffbasen die basisch substituierten Barbitursauren 3-5 hergestellt. Von den 27 synthetisierten Racematen konnten 17 mit Camphersulfonsaure in die Enantiomere gespalten werden.Monoalkylated malonates were condensed with N-monosubstituted ureas to yield the 5-monosubstituted barbituric acids 1, which were reacted to the 5-bromobarbituric acids2. From 2 the barbituric acids 3-5 having basic substituents were obtained by nucleophilic substitution with N-bases. From the 27 racemates obtained, 17 were resolved into the enantiomers with camphersulfonic acid. Im Gegensatz zu den herkommlichen Barbitursauren fanden solche mit heterozyklischen Substituenten in 5-Stellung bisher vergleichsweise wenig Interesse. Die Einfiihrung stickstoffhaltiger Substituenten in 5-Position ergab anfangs pharmakologisch unwirksame Verbindungen'). Erst die Darstellung von Barbitursauren, bei denen das N-Atom eines basischen Substituenten direkt mit dem C-5 verkniipft ist, fiihrte zu pharmakologisch wirksamen Produkten. Eine Reihe von Barbitursauren dieser Art wurde zwischen 1930 und 1960, vor allem von Geba~er')')~) und Go1dhahn6)'), synthetisiert. +) Herrn Prof. Dr. Engelbert Grafzum 60. Geburtstag gewidmet.

Chiral recognition ability and solvent versatility of bonded amylose tris(3,5‐dimethylphenylcarbamate) chiral stationary phase: Enantioselective liquid chromatographic resolution of racemic N‐alkylated barbiturates and thalidomide analogs

“…All N-alkylated barbiturates: 5-ethyl-1-methyl-5-n-propyl barbituric acid (1), 1-methyl-5-(2-propyl)-5-(n-propyl) barbituric acid (2), 1,5dimethyl-5-ethyl barbituric acid (3), 1,5-dimethyl-5-phenyl barbituric acid (4) also known as methylheptobarbital or methyleudan, 5-cyclohexyl-5-ethyl-1-methyl-barbituric acid (5), 5-(1-cyclopenten-1-yl)-5-ethyl-1-methyl barbituric acid (6), 1-methyl-5-phenyl-5-propyl barbituric acid (7), 5-(1cyclohexen-1-yl)-1,5-dimethyl barbituric acid (8), 1-methyl-5-butyl-5-phenyl barbituric acid (9), 1-ethyl-5-methyl-5-piperidyl barbituric acid (10), 5-(1-cyclohexen-1-yl)-1ethyl-5-methyl barbituric acid (11), 5-(1-cyclohexen-1-yl)-5methyl-1-propyl barbituric acid (12), and the 3-alkylated analogs of thalidomide: methyl, ethyl, and propyl thalidomide (13,14, and 15, respectively) as racemates and separate enantiomers were given as a gift by Prof. Joachim Knabe, University of Saarbruecken, Germany. 1,2 The absolute configuration and the sign of optical rotation of racemates were confirmed by injecting well-known configuration of separate enantiomers.…”

“…They have been used as sedatives, hypnotics, anesthetics, and anticonvulsants. 1,2 On the other hand, thalidomide analogs have potent effects upon the a tumor necrosis factor (TNF-a). Some analogs have far stronger TNF-a effects, while others are potent nonsteroidal androgen antagonists or have antiangiogenesis properties.…”

Exploring solvent versatility in immobilized cellulose‐based chiral stationary phase for the enantioselective liquid chromatographic resolution of racemates

“…All N-alkylated barbiturates: (12), and the analogs of thalidomide alkylated in position 3 of the piperidin-2,6-dione ring: methyl, ethyl, and propyl thalidomide (13, 14, and 15, respectively) as racemates and separate enantiomers were given as a gift by Professor Joa- chim Knabe, University of Saarbruecken, Germany [28,29]. The absolute configuration and the sign of optical rotation of racemates were confirmed by injecting wellknown configuration of separate enantiomers.…”

The Aminobarbituric Acid−Hydantoin Rearrangement

“…The solvent system used for TLC was toluene/acetone/methanol (5:3:2). Barbituric acids 1a − g , 6 were prepared following literature procedures. − …”