- One-pot reductive amination of carboxylic acids: a sustainable method for primary amine synthesis
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The reductive amination of carboxylic acids is a very green, efficient and sustainable method for the production of (bio-based) amines. However, with current technology, this reaction requires two to three reaction steps. Here, we report the first (heterogeneous) catalytic system for the one-pot reductive amination of carboxylic acids to amines, with solely H2 and NH3 as the reactants. This reaction can be performed with relatively cheap ruthenium-tungsten bimetallic catalysts in the green and benign solvent cyclopentyl methyl ether (CPME). Selectivities of up to 99% for the primary amine could be achieved at high conversions. Additionally, the catalyst is recyclable and tolerant for common impurities such as water and cations (e.g. sodium carboxylate).
- Coeck, Robin,De Vos, Dirk E.
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supporting information
p. 5105 - 5114
(2020/08/25)
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- Mild Amide-Cleavage Reaction Mediated by Electrophilic Benzylation
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An extremely mild method for amide-cleavage by using the triazine-based benzylating reagent 4-(4,6-diphenoxy-1,3,5-triazin-2-yl)-4-benzylmorpholinium trifluoromethanesulfonate (DPT-BM), which spontaneously releases benzyl cation species when being dissolved at room temperature, has been developed. O-Benzylation of the amide with DPT-BM and the subsequent hydrolysis of the resulting intermediate benzyl imidate salt afford the corresponding amine and benzyl ester, which can be converted by hydrogenolysis into a carboxylic acid under neutral conditions. O-Benzylation proceeds depending on both steric and electronic factors around the amide group. Thus, some amides have been selectively cleaved over other amides. Furthermore, intramolecular chemoselective cleavage of an amide group in the presence of an ester group was achieved. Such selective hydrolytic reactions cannot be performed with Meerwein reagents as well as under acidic or basic hydrolytic conditions.
- Yamada, Kohei,Karuo, Yukiko,Tsukada, Yuichi,Kunishima, Munetaka
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supporting information
p. 14042 - 14047
(2016/09/21)
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- Synthesis and evaluation of antiallodynic and anticonvulsant activity of novel amide and urea derivatives of valproic acid analogues
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Valproic acid (VPA, 1) is a major broad spectrum antiepileptic and central nervous system drug widely used to treat epilepsy, bipolar disorder, and migraine. VPA's clinical use is limited by two severe and lifethreatening side effects, teratogenicity and hepatotoxicity. A number of VPA analogues and their amide, N-methylamide and urea derivatives, were synthesized and evaluated in animal models of neuropathic pain and epilepsy. Among these, two amide and two urea derivatives of 1 showed the highest potency as antineuropathic pain compounds, with ED50 values of 49 and 51 mg/kg for the amides (19 and 20) and 49 and 74 mg/kg for the urea derivatives (29 and 33), respectively. 19, 20, and 29 were equipotent to gabapentin, a leading drug for the treatment of neuropathic pain. These data indicate strong potential for the above-mentioned novel compounds as candidates for future drug development for the treatment of neuropathic pain. 2009 American Chemical Society.
- Kaufmann, Dan,Bialer, Meir,Shimshoni, Jakob Avi,Devor, Marshall,Yagen, Boris
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experimental part
p. 7236 - 7248
(2010/07/04)
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- Potent anticonvulsant urea derivatives of constitutional isomers of valproic acid
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Valproic acid (VPA) is a major antiepileptic drug (AED); however, its use is limited by two life-threatening side effects: teratogenicity and hepatotoxicity. Several constitutional isomers of VPA and their amide and urea derivatives were synthesized and evaluated in three different anticonvulsant animal models and a mouse model for AED-induced teratogenicity. The urea derivatives of three VPA constitutional isomers propylisopropylacetylurea, diisopropylacetylurea, and 2-ethyl-3-methyl-pentanoylurea displayed a broad spectrum of anticonvulsant activity in rats with a clear superiority over their corresponding amides and acids. Enanatiomers of propylisopropylacetylurea and propylisopropylacetamide revealed enantioselective anticonvulsant activity, whereas only enantiomers of propylisopropylacetylurea displayed enantioselective teratogenicity. These potent urea derivatives caused neural tube defects, but only at doses markedly exceeding their effective dose, whereas VPA showed no separation between its anticonvulsant activity and teratogenicity. The broad spectrum of anticonvulsant activity of the urea derivatives coupled with their wide safety margin make them potential candidates to become new, potent AEDs.
- Shimshoni, Jakob Avi,Bialer, Meir,Wlodarczyk, Bogdan,Finnell, Richard H.,Yagen, Boris
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p. 6419 - 6427
(2008/03/30)
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- Prodrugs containing novel bio-cleavable linkers
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The invention provides the compounds of formula (I) or pharmaceutically acceptable salts thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of formula I or intermediates thereof and one more of pharmaceutically acceptable carriers, vehicles or diluents. The invention further provides methods of preparation and methods of use of prodrugs including NO-releasing prodrugs, double prodrugs and mutual prodrugs comprising the compounds of formula I.
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Page/Page column 114; 143
(2008/06/13)
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- Examining the correlations between GSK-3 inhibitory properties and anti-convulsant efficacy of valproate and valproate-related compounds
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A family of compounds based upon the chemical structure of valproate were synthesized and assayed for their ability to inhibit glycogen synthase kinase (GSK)-3 α and β activity in vitro. A family of compounds based upon the chemical structure of valproate were synthesized and assayed for their ability to inhibit glycogen synthase kinase (GSK)-3 α and β activity in vitro. This data is correlated to the known anti-convulsant properties of these compounds in order to determine the potential role of GSK-3 inhibition in the therapeutic efficacy of these drugs.
- Werstuck, Geoff H.,Kim, Anna J.,Brenstrum, Timothy,Ohnmacht, Stephan A.,Panna, Ella,Capretta, Alfredo
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p. 5465 - 5467
(2007/10/03)
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