- Reactive metabolites of desipramine and clomipramine: The kinetics of formation and reactivity with DNA
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Tricyclic antidepressants (TCAs), along with phenothyazines and some industrial chemicals, are shown to react with enzymes that exhibit peroxidase activity. These reactions result in the formation of reactive intermediates having unpaired electrons. The peroxidase oxidation and reactivity of two TCAs, desipramine and clomipramine, were investigated. As a model of peroxidase, horseradish peroxidase (HRP) was employed. The products of the peroxidase catalyzed oxidation of desipramine and clomipramine were identified as N-dealkylated compounds iminodibenzyl and 3-chloroiminodibenzyl using the GC/MS technique. Both drugs formed broad UV/vis absorption spectra in the presence of HRP and H2O2, indicating the formation of a radical cations - reactive intermediate of the oxidation reaction. The dynamics of the formation of the desipramine intermediate was studied using UV/vis spectroscopy. The extinction coefficient was measured for the reactive intermediate, 7.80 × 103 M-1 cm-1, as well as the apparent Michaelis-Menten and catalytic constants, 4.4 mM and 2.3 s-1, respectively. Both desipramine and clomipramine degraded DNA in the presence of HRP/H2O2, as was revealed by agarose gel electrophoresis and PCI extraction. Manipulating the kinetic parameters of drug's radical formation and determining the extent of degradation to biomolecules could be potentially used for designing effective agents exhibiting specific reactivity.
- Korobkova, Ekaterina A.,Nemeth, John,Cadougan, Mikeisha,Venkatratnam, Abhishek,Bassit, Mohanram,Azar, Nikolay
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- Combined KOH/BEt3Catalyst for Selective Deaminative Hydroboration of Aromatic Carboxamides for Construction of Luminophores
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The selective catalytic C-N bond cleavage of amides into value-added amine products is a desirable but challenging transformation. Molecules containing iminodibenzyl motifs are prevalent in pharmaceutical molecules and functional materials. Here we established a combined KOH/BEt3 catalyst for deaminative hydroboration of acyl-iminodibenzyl derivatives, including nonheterocyclic carboxamides, to the corresponding amines. This novel transition-metal-free methodology was also applied to the construction of Clomipramine and luminophores.
- Li, Jinshan,Wang, Jiali,Yang, Jianguo,Yao, Wubing,Zhong, Aiguo
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supporting information
p. 8086 - 8090
(2020/11/03)
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- High-purity clomipamine hydrochloride and preparation method thereof
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The invention relates to high-purity clomipamine hydrochloride and a preparation method thereof. Specifically, the preparation method comprises the following steps: reacting bromochloropropane with dimethylamine in the presence of alkali to obtain an intermediate I compound; adding 3-chlor-5-acetyl diphenyl imide and potassium hydroxide into toluene, and heating for reaction to obtain an intermediate II; adding potassium carbonate, potassium hydroxide into the intermediate II, and heating reactants, then adding a mixed solution of the intermediate I compound and methylbenzene, continuously heating to finish the reaction, then cooling the reaction solution, and adding water for extraction to obtain an organic layer containing clomipamine; concentrating the previous product under reduced pressure to obtain an oily substance, adding acetone, dropwise adding hydrochloric acid for acidification, crystallizing, centrifuging to obtain a crystal, and drying to obtain a clomipamine hydrochloride crude product; and adding the obtained clomipamine hydrochloride crude product and a solvent into a reaction kettle, heating for dissolving, adding medicinal carbon for reflux decolorization treatment, filtering for decarburization, cooling for crystallization, filtering for crystallization, and drying to obtain a clomipamine hydrochloride finished product. The method has the effects described in the specification.
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Paragraph 0082; 0089; 0094-0096; 0106; 0110-0111; 0118; 0122
(2020/11/23)
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- Hydride-catalyzed selectively reductive cleavage of unactivated tertiary amides using hydrosilane
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The first hydride-catalyzed reductive cleavage of various unactivated tertiary amides, including the biologically active aryl-phenazine carboxamides and the challenging non-heterocyclic carbonyl functions, using low-cost hydrosilane as a reducing reagent has been developed. The novel catalyst system exhibits high efficiency and exclusive selectivity, providing the desired amines in useful to excellent yields under mild conditions. Overall, this transition metal-free process may offer a versatile alternative to currently employed expensive reducing reagents, high-pressure hydrogen or metal systems for the selective reductive cleavage of amides.
- Yao, Wubing,Li, Rongrong,Yang, Jianguo,Hao, Feiyue
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p. 3874 - 3878
(2019/08/07)
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- Enhancing Reactivity and Selectivity of Aryl Bromides: A Complementary Approach to Dibenzo[b,f]azepine Derivatives
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Dihydrodibenzo[b,f]azepines and dibenzo[b,f]azepines can be efficiently synthesized from aryl bromides, o-bromoanilines and norbornene or norbornadiene by means of palladium catalysis. This protocol gives access to dibenzo[b,f]azepine core containing a variety of electron-withdrawing substituents on both aromatic rings and complements the previously reported methodology where electron rich aryl iodides were preferentially used. The presence of KI, even in sub-stoichiometric amount, is crucial for this three-component reaction. The proper addition of iodide anions has a dramatic effect on reaction rate and selectivity. A formal three-step synthesis of the tricyclic antidepressant Clomipramine (Anafranil) is also described.
- Casnati, Alessandra,Fontana, Marco,Coruzzi, Giovanni,Aresta, Brunella Maria,Corriero, Nicola,Maggi, Raimondo,Maestri, Giovanni,Motti, Elena,Della Ca', Nicola
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p. 4346 - 4352
(2018/09/14)
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- A disubstituted amide derivatives decarbonylation hydrogenation green new method (by machine translation)
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The invention relates to a high efficiency, high selectivity of the disubstituted amide derivatives of decarbonylation hydrogenation reaction green new method. For the first time to the metallic compound triethylborane as catalyst, under mild conditions can be conveniently catalytic N, N - di-aryl substituted amide and its derivative and cheap and easy to obtain organic silicon reagent selective preparation of secondary organic amine product. Compared with the traditional method, the new method generally has the wide substrate universality, functional group compatibility outstanding, simple operation and the like. For the first time in order to realize the organic silicon reagent as reducing agent and amide compounds decarbonylation hydrogenation reaction, is the reduction of amides and derivatives thereof, in particular the organic light-emitting diodes (OLEDs) material unit - diaryl amine compound of the laboratory preparation or industrial production provides a brand-new "green" response strategies. (by machine translation)
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Paragraph 0018; 0019; 0020; 0021
(2018/02/04)
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- Reductive cleavage of amides to alcohols and amines catalyzed by well-defined bimetallic molybdenum complexes
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Triple bonds do it! The molybdenum-catalyzed Ci-N bond cleavage of organic amides with hydrosilanes to produce alcohols and amines has been investigated. This work complements previously established protocols that lead to the cleavage of the Ci-O bond. Modified triply bonded dimolybdenum(III) alkoxides have been found to be crucial for tuning the selectivity to Ci-N bond cleavage (see figure). Copyright
- Krackl, Sebastian,Someya, Chika I.,Enthaler, Stephan
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supporting information
p. 15267 - 15271
(2013/01/15)
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- Synthesis of substituted 10,11-dihydro-5H-dibenz[b,f]azepines; key synthons in syntheses of pharmaceutically active compounds
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Substituted 10,11-dihydro-5H-dibenz[b,f]azepines are key synthons in the syntheses of a number of pharmaceutically active compounds such as imipramine, chlorimipramine, and desimipramine analogues. A facile synthesis of substituted 10,11-dihydro-5H-dibenz[b,f]azepines is described, starting out from commercially available 2-bromotoluenes or 2-nitrotoluenes. Initial α-bromination with N-bromosuccinimide and subsequent reaction with triethylphosphite afforded the corresponding benzyl phosphonic ester derivatives. After reaction with benzaldehyde derivatives, the expected Horner-Emmons reaction products were obtained. Hydrogenation gave the amino derivatives which were transformed into the corresponding formamides. Under Goldberg conditions [1], the final ring closing step was performed to give the substituted 10,11-dihydro-5H-dibenz[b,f]azepines in 46-75% yield.
- Jorgensen, Tine Krogh,Andersen, Knud Erik,Lau, Jesper,Madsen, Peter,Huusfeldt, Per Olaf
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- Preparation of asymmetric iminodibenzyl compounds
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Iminodibenzyl derivatives of the formula: SPC1 Wherein R and R1 each represent hydrogen, halogen, amino, sulfamoyl, lower alkyl, lower alkoxy or lower alkanoyl, provided that R and R1 can not both be hydrogen and when R and R1 are the same, they are located at positions asymmetric to each other, are produced in high purity and yield by a series of reactions which proceed through novel 2,2'-dinitrostilbene or 2,2'-diaminostilbene and 2,2'-diaminodibenzyl derivatives. The reaction sequence involves condensation, reduction and ring-closure reactions to give asymmetric as well as symmetric iminodibenzyl derivatives. The resulting iminodibenzyl derivatives may be converted to useful pharmaceutical compounds having anti-depressant, analgesic or anti-allergic properties.
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