547.94:547.834.2 N. Z. Baibulatova, L. V. Spirikhin, M. S. Yunusov, N. S. Makara, N. Zh. Baschenko, and V. A. Dokichev Derivatives of N-(2-hydroxyethyl)cytisine, N-(2-hydroxypropyl)-, N-(2-hydroxy-2-(1-adamantyl)ethyl)-, and N-(2-hydroxy-2-phenylethyl)cytisine, were synthesized by reduction of N-(2-oxopropyl)-, N-(2-oxo-2-(1-adamantyl)ethyl)-and N-(2-oxo-2-phenylethyl)cytisine with metal hydrides. The antiarrhythmic and analgesic activities of the prepared compounds were investigated.Cytisine (1) and its derivatives are attractive to researchers owing to their broad spectrum of physiological activity (spasmolytic [1], insecticidal [2], cholinergic [3], analgesic [4]) and the ability to use them in catalytic reactions as optically active ligands [5]. We recently showed that N-(2-hydroxyethyl)cytisine has low toxicity and exhibits high antiarrhythmic activity compared with known antiarrhythmics [6,7].The goal of the present work was to synthesize new cytisine derivatives [8][9][10][11] and to study the structure-activity (antiarrhythmic) relationship for N-(2-hydroxyethyl)cytisine derivatives. Thus, we synthesized N-(2-hydroxypropyl)-(4a), N-(2-hydroxy-2-(1-adamantyl)ethyl)-(4b), and N-(2-hydroxy-2-phenylethyl)cytisine (4c) via reduction of the corresponding 2-alkyl-or 2-phenyl substituted N-(2-oxoethyl)cytisines 3a-c, which were prepared by reacting 1 and bromoketones 2a-c. R = Me (a), Ad (b), Ph (c)Ketones 3a-c were prepared by reacting 1 with bromoketones [bromoacetone (2a), 1-adamantyl-2-bromomethylketone (2b), bromoacetophenone (2c)] in anhydrous acetone in the presence of K 2 CO 3 for 1 h in 95-99% yields.The reduction of these ketones with NaBH 4 , LiAlH 4 , (i-Bu) 2 AlH, and AlH 3 ·N(Me) 3 was studied in order to investigate the effect of the optically active center of cytisine and the nature of the metal hydride on the new asymmetric center formed by conversion of the carbonyl in 3a-c into a secondary alcohol.
5 Nitropentan 2 one reacts with methylamine and formaldehyde according to the Mannich reaction pattern to give 5 hexahydropyrimidinylcarbonyl substituted 1 nitro 3,7 diazabi cyclo[3.3.1]nonane in one experimental stage. When methyl 3 R 4 nitrobutanoates are used, the reaction stops after the formation of substituted 5 nitrohexahydropyrimidines in 40-98% yields.
547.94 S. P. Ivanov, L. V. Spirikhin, and V. A. Dokichev* Diastereomers of N(12)-(2-hydroxy-2-phenylethyl)cytisine were synthesized by reduction of N(12)-(2-oxo-2-phenylethyl)cytisine by Yamamoto reagent. Their structures were solved using x-ray structure analysis.
Diastereomers of N-(2-(1-adamantyl)-2-hydroxyethyl)cytisine were synthesized by reduction of N-(2-(1-adamantyl)-2-oxoethyl)cytisine with NaBH 4 . Their structures were established using x-ray structure analysis.
Pyrimidine derivatives R 0510Reaction of γ-Nitroketones and Methyl 4-Nitrobutanoates with Formaldehyde and Primary Amines. -Condensation of sterically non-hindered 5-nitropentan-2-one with Me-NH2 and formaldehyde affords pyrimidinylcarbonyl-substituted diazabicyclononane (VII) in one experimental stage. Similar reaction of 4-nitrobutanoates (I) stops after formation of hexahydropyrimidines (IV). -(SHAKIROV*, R. R.; VLASOVA, L. I.; SHISHKIN, D. V.; YARMUKHAMEDOV, N. N.; BAYBULATOVA, N. Z.; SEMESKO, D. G.; DOKICHEV, V. A.; TOMILOV, Y. V.; Russ.
SHORT COMMUNICATIONS(-)-Cytisine {I, (1R,5S)-1,2,3,4,5,6-hexahydro-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one} is an accessible alkaloid of the quinolizidine series. It attracts interest due to its broad spectrum of physiological activity (spasmolytic, cholinergic, analgesic) which originates from its high affinity for nicotine acetylcholine receptors (nAChRs) [1][2][3]. We found that introduction of a 2-hydroxyethyl fragment into cytisine molecule gives rise to high antiarrhythmic activity which was not found previously for cytisine derivatives; in addition, the toxicity of the resulting compound was lower than that of known antiarrhythmics [4,5].We succeeded in developing a new one-pot procedure for the synthesis of 1,3-bis(cytisinyl)propan-2-ol II from cytisine (I) and 1-chloro-2,3-epoxypropane. Compound II was synthesized previously in two steps with an overall yield of 34% [6]. By heating cytisine (I) with 1-chloro-2,3-epoxypropane at a molar ratio of 2 : 1 in MeOH-H 2 O (volume ratio 3 : 2) we obtained alcohol II in 80% yield with high selectivity. Compound II may be interesting not only as physiologically active substance but also as reagent for asymmetric syntheses. When methanol, acetone, or benzene was used as solvent, either a complex mixture of products was formed or no reaction occurred.The structure of compound II was confirmed by the 1 H and 13 C NMR spectra; signals were assigned using HH-COSY and CH-CORR techniques. In the 13 C NMR spectrum of II we observed two sets of signals from carbon atoms in the cytisine fragments. Exceptions were magnetically equivalent C 8 and C 8′ nuclei which resonated at δ C 25.73 ppm.(1R,5R,1′R,5′R)-3,3′-(2-Hydroxypropane-1,3-diyl) bis(1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido-[1,2-a][1,5]diazocin-8-one) (II). 1-Chloro-2,3-epoxypropane, 0.24 g (2.63 mmol), was added to 1.0 g (5.26 mmol) of cytisine in 20 ml of a mixture of methanol with water (volume ratio 3 : 2). The mixture was heated for 2 h under reflux, the solvent was removed under reduced pressure, 6 ml of water, 20 ml of chloroform, and ~1 ml of 20% aqueous sodium hydroxide were added to the residue (until pH 8-9), and the mixture was extracted with chloroform (3 × 25 ml). The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by chromatography on silica gel using chloroform-methanol (9 : 1) as eluent. Yield 0.92 g (80%), colorless amorphous hygroscopic powder, R f 0.43 (CH 3 Cl-MeOH, 9 : 1), [α] D 20 = -230° (c = 0.175, CHCl 3 ). IR spectrum, ν, cm -1 : 3080-3600 (OH),
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