- DIHYDROPYRIDONE AMIDES AS P2X7 MODULATORS
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Compounds of the formula I: or pharmaceutically acceptable salts thereof, wherein m, n, R1, R2, R3, R4 and R5 are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with the P2X7 purinergic receptor.
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Page/Page column 23
(2010/07/04)
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- DIHYDROPYRIDONE UREAS AS P2X7 MODULATORS
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Compounds of the formula I: or pharmaceutically acceptable salts thereof, wherein m, n, R1, R2, R3, R4 and R5 are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with the P2X7 purinergic receptor.
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Page/Page column 50
(2010/07/04)
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- Diastereomeric reissert compounds of isoquinoline and 6,7-dimethoxy-3,4- dihydroisoquinoline in stereoselective synthesis
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(Chemical Equation Presented) Chiral acid chlorides were reacted with isoquinoline and 6,7-dimethoxy-3,4-dihydroisoquinoline to form diastereomeric Reissert compounds 8-11 and 18-21, respectively. The best diastereoselectivity (80:20) was achieved in formation of the 9-phenylmenthyl derivative 20. The diastereomers of 2-l-menthoxy-carbonyl-1,2-dihydroisoquinaldonitriles (S)-8/(R)-8), formed in equal amounts, were inseparable. However, the individual diastereomers of 2-cholesteryloxycarbonyl-1,2-dihydroisoquinaldonitriles ((R)-11 and (5)-11) and the 2-l-menthoxycarbonyl-6,7-dimethoxy-1,2,3,4- tetrahydroisoquinaldonitriles ((S)-19/(R)-19)) were each readily purified. (S)-8/(R)-8 (1:1) via the corresponding anions (NaH, -40°C, DMF) with pivaldehyde yielded in 82:18 predominance the S-diastereomer of 1-isoquinolyl tert-butyl carbinyl l-menthyl carbonate ((S)-12), which was obtained in pure form by a single recrystallization; hydrolysis produced 99% pure S-(-)-1-isoquinolyl tert-butyl carbinol [(S)-16]. Reactions of the anions of diastereomeric Reissert compounds, either as mixtures or pure single species, with aromatic aldehydes and alkyl halides proceeded with at best modest selectivity (diastereomeric ratios up to 66:34 and 72:28, respectively). Therefore, it is concluded that the Reissert anions are either planar or rapidly inverting tetrahedral structures.
- Gibson, Harry W.,Berg, Michael A. G.,Dickson, Jennifer Clifton,Lecavalier, Pierre R.,Wang, Hong,Merola, Joseph S.
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p. 5759 - 5770
(2008/02/11)
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- Reagent-controlled diastereoselective aminations with a new chiral nosyloxycarbamate
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The synthesis of a new chiral nosyloxycarbamate derived from Helmchen's auxiliary is described. Reactions performed with this aminating reagent successfully give the formation of diastereomeric allylic carbamates or diastereomeric aziridines starting from different kinds of olefins.
- Fioravanti, Stefania,Morreale, Alberto,Pellacani, Lucio,Tardella, Paolo A.
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p. 3031 - 3034
(2007/10/03)
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- Total synthesis of (-)-epibatidine using an asymmetric Diels-Alder reaction with a chiral n-acylnitroso dienophile
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An asymmetric total synthesis of (-)-epibatidine (1), isolated from the skin of the Ecuadorian poison frog, Epipedobates tricolor, of the family Dendrobatidae, has been achieved by virtue of the development of asymmetric hereto Diels-Alder (D-A) cycloaddition with an N-acylnitroso dienophile bearing the optically active 8-arylmenthol as a chiral source. Thus, in situ oxidation of the hydroxamic acid ent-12f incorporating the (1S,2R,5S)-8-(2- naphthyl)menthyl auxiliary was performed using the Swern conditions to produce the acylnitroso dienophile, which reacted at once with 2-chloro-5- (1,5-cyclohexadienyl)pyridine (7) to provide the (1S,4R)-meta-aza cycloadduct 24 as a major diastereoisomer. The observed facial diastereoselectivity is consistent with a transition-state model with the naphthyl group in 'stacked' position and with the acylnitroso group in the s-cis conformation, wherein π attractive interaction between the naphthyl and nitrosocarbonyl groups may contribute to facial control. Compound 24 underwent hydrogenation followed by removal of the chiral auxiliary with LiH2NBH3 and reductive cleavage of the N-O bond with Mo(CO)6 to give the amino alcohol derivative 29, which was converted to (-)-epibatidine via bromination followed by cyclization.
- Aoyagi, Sakae,Tanaka, Ryuta,Naruse, Masaichi,Kibayashi, Chihiro
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p. 8397 - 8406
(2007/10/03)
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- Lewis acid-promoted asymmetric conjugate allylation of N-acyl-2,3-dihydro-4-pyridones induced by intramolecular π interactions
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Lewis acid-promoted conjugate addition reaction of an allylsilane to a series of the chiral 8-arylmenthol-derived N-acyl-2,3-dihydro-4-pyridones leads to the 2-allyl-4-piperidones with moderate to high levels of asymmetric induction, indicating π-stacking contribution to chirality control. This methodology was applied to the asymmetric synthesis of (-)-N-methylconiine. Copyright (C) 1996 Elsevier Science Ltd.
- Sato, Masayuki,Aoyagi, Sakae,Yago, Seiji,Kibayashi, Chihiro
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p. 9063 - 9066
(2007/10/03)
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- Asymmetric synthesis of 2-alkyl(aryl)-2,3-dihydro-4-pyridones by addition of Grignard reagents to chiral 1-acyl-4-methoxypyridinium salts
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The asymmetric synthesis of 2-alkyl(aryl)-2,3-dihydro-4-pyridones 3 by addition of various Grignard reagents to chiral 1-acyl-4-methoxypyridinium salts was studied in detail. Chiral pyridinium salts formed from 4-methoxy-3-(triisopropylsilyl)pyridine (2f), and (-)-8-arylmenthyl chloroformates, or (-)-trans-2-(α-cumyl)cyclohexyl chloroformate, gave the best results, with diastereomeric selectivities ranging from 60 to 94%. When 4-methoxy-3-(trialkylstannyl)pyridines were used, destannylated 2-alkyl-2,3-dihydropyridones 3a resulted in good yield. The size of the C-3 substituent, the auxiliary, the solvent, the reaction temperature, and the structure of the Grignard reagent were varied to determine their effect on the yield and the degree of asymmetric induction. The chiral auxiliary and the C-3 triisopropylsilyl group can be removed from 3f, and the auxiliary recovered, on treatment with sodium methoxide in methanol followed by aqueous acid. The resulting 2,3-dihydropyridones 8 are useful chiral building blocks for the enantioselective synthesis of various alkaloids.
- Comins, Daniel L.,Joseph, Sajan P.,Goehring, R. Richard
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p. 4719 - 4728
(2007/10/02)
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- NMR detection of N-acyliminium ion intermediates generated from α-alkoxycarbamates
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The N-acyliminium ion intermediates generated from α-alkoxycarbamates in the presence of Lewis acids were for the First time detected by 1 H and 13C NMR. It was confirmed that there is an equilibrium between the starting carbamate and the intermediate and that the equilibrium is highly dependent upon a Lewis acid. By using the saturation transfer method, the rate constant for the formation of the intermediate was obtained. NOE experiments revealed that ((4-methylphenyl)methylene)methyl(methoxycarbonyl)ammonium methyltrifluoroborate 6 has E-geometry.
- Yamamoto, Yoshinori,Nakada, Tomohisa,Nemoto, Hisao
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p. 121 - 125
(2007/10/02)
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