- Molecular structure of clonidine: Gas-phase electron diffraction, single-crystal X-ray diffraction and quantum chemical studies
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This study presents the first determination of the molecular structure of the antihypertensive drug clonidine in the gas phase using gas electron diffraction (GED). The refinement was supported by quantum chemical calculations (QCs). The tautomeric and conformational distribution was investigated theoretically, providing an explanation for the presence of the single conformer in the gas phase. The molecular conformation of clonidine has been shown to have a nearly perpendicular arrangement of the phenyl and imidazolidine rings as described by the torsion angle C2-N6-C7-C8 = -72(6)°. The following structural parameters were obtained (bond lengths in Angstroms and bond angles in degrees with 3σ in parentheses): r(CHH-CHH) = 1.549(7), r(CHH-NH)av = 1.470(7), r(NH-C)av = 1.388(2), r(CN) = 1.286(7), r(C-N) = 1.388(2), r(CzC)av = 1.403(2), r(C-Cl)av = 1.737(2); ∠(NH-C-NH) = 108.1(11), ∠(CHH-NH-C)av = 109.7(12), ∠(CHH-CHH-NH)av = 100.9(12), ∠(C-NC) = 122.5(12), ∠(CClzCzCCl) = 114.9(2), and ∠(CHzCClzC)av = 123.1(2). The standard enthalpy of formation of clonidine in the gas phase was calculated using G4 theory with both atomisation and isodesmic reaction approaches, yielding the corresponding value of. The molecular structure of clonidine in the solid phase was determined using X-ray diffraction (XRD). Clonidine crystallizes in the monoclinic space group P21/c as a twinned crystal. The imino-tautomer, as an equimolar mixture of the two conformers with geometries close to the enantiomeric pair, is present in the solid phase. The identical conformers are linked into centrosymmetric dimers by paired N-H?N hydrogen bonds. The geometries of gaseous and solid clonidine differ especially in the immediate vicinity of the intermolecular hydrogen bonds formed in the crystal.
- Kolesnikova, Inna N.,Rykov, Anatolii N.,Shishkov, Igor F.,Tafeenko, Victor A.,Aslanov, Leonid A.
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- Heterocyclic compounds as FGFR4 inhibitors
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The present invention provides heterocyclic compounds as selective inhibitors of fibroblast growth factor receptor 4 (FGFR4), pharmaceutical compositions containing the compounds, methods of preparingthe compounds, and methods of treating cell proliferative diseases, such as cancer, using the compounds of the invention.
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Paragraph 0257-0262
(2021/02/10)
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- A preparation method of the clonidine hydrochloride
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The invention discloses a method for preparing the clonidine hydrochloride, including intermediates 1 synthesis, intermediate 2 synthesis and clonidine hydrochloride synthetic three steps, the present invention in order to 2, 6 - dichloroaniline as raw materials, through the hydroformylation reaction get intermediate 1, "one-pot" get clonidine free base, finally with hydrogen chloride ethanol solution into salt clonidine hydrochloride. By processing the raw material synthetic process, by utilizing the free alkali in the course of refining into salt after adjusting pH, and the clonidine hydrochloride is used for purification of the pulping process control such as ethyl acetate, to obtain a high-purity clonidine hydrochloride preparation method. The method not only improves the product purity and yield, impurity can also effectively control, but also greatly reducing the cost, simplifying the process, is more suitable for industrial production.
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Paragraph 0048; 0055; 0058; 0061; 0062
(2018/04/28)
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- Efficient synthesis of 2-arylamino-2-imidazolines and 2-aminobenzimidazoles with aminoiminomethanesulfonic acid derivatives
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A highly efficient synthesis of 2-arylamino-2-imidazolines and 2-aminobenzimidazoles from aminoiminomethanesulfonic acid derivatives is described. The method is simple and practical, generating imidazoline and benzimidazoline derivatives in excellent isolated yields.
- Mohanazadeh, Farajollah,Nami, Navabe,Hosseini, Samine Sadat
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experimental part
p. 1055 - 1058
(2012/01/04)
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- A convenient method for the synthesis of 2-amino substituted aza-heterocycles from N,N′-disubstituted thioureas using TsCl/NaOH
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p-Toluenesulfonyl chloride (TsCl)/NaOH has been introduced as reagent combination for the synthesis of 2-amino-oxa- or 2-amino-thiazolidines from N-(2-hydroxyethyl)-thioureas, but its general application in heterocycle synthesis has not been investigated. In this paper the convenient and efficient synthesis of a variety of 2-amino-substituted 1-aza 3-(aza, oxo or thio) heterocycles of different substitution and ring sizes is described. The application of polymer-supported TsCl facilitates work-up and renders the reaction conditions very suitable for parallel or robot synthesis. Graphical Abstract
- Heinelt, Uwe,Schultheis, Daniela,J?ger, Siegfried,Lindenmaier, Marion,Pollex, Annett,Beckmann, Henning S.G.
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p. 9883 - 9888
(2007/10/03)
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- Process for synthesizing heterocyclic compounds
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The invention provides the process illustrated in scheme 1 for synthesizing heterocyclic compounds of formula I. In the process, an isothiocyanate of formula II is initially reacted with a primary amine of formula III to give a thiourea of formula IV. Subsequently, the thiourea of formula IV is converted to the corresponding heterocycle of formula I using a base and a sulfonyl chloride.
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Page/Page column 13
(2008/06/13)
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- TREATMENT OF URINARY INCONTINENCE BY ADMINISTRATION OF ALPHA 1L-ADRENOCEPTOR AGONISTS
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The present invention relates to the use of α lL-agonists for treating urinary incontinence.
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- Process for making 2-amino-2-imidazoline, guanidine and 2-amino-3,4,5,6-tetrahydropyrimidine derivatives
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The present invention provides a process for making 2-amino-2-imidazoline, guanidine, and 2-amino-3,4,5,6-tetrahydroyrimidine derivatives by preparing the corresponding activated 2-thio-subsituted-2-derivative in a two-step, one-pot procedure and by further reacting yields this isolated derivative with the appropriate amine or its salts in the presence of a proton source. The present process allows for the preparation of 2-amino-2-imidazolines, quanidines, and 2-amino-3,4,5,6-tetrahydropyrimidines under reaction conditions that eliminate the need for lengthy, costly, or multiple low yielding steps, and highly toxic reactants. This process allows for improved yields and product purity and provides additional synthetic flexibility.
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- N-Nitroso Compounds. Part 2. The Synthesis of N-Nitrosoclonidine and its Decomposition in Aqueous Acidic Media
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Clonidine, a 2-arylaminoimidazoline, undergoes nitrosation in aqueous nitrous acid to form N-nitrosoclonidine. 1H NMR spectroscopy reveals that the nitroso group resides on one of the imidazoline nitrogen atoms.N-Nitrosoclonidine decomposes in aqueous acidic media to form quantitatively clonidine and nitrous acid.The reaction is acid catalysed and involves rate-limiting protonation of the substrate, as revealed by a solvent deuterium isotope effect, k2H/k2D, of 1.2 and the independence of the rate of denitrosation upon the presence of Cl- or SCN-.The Broensted α exponent for general acid-catalysis is 0.5.The mechanism is contrasted to that for analogous 2-arylimidazolines, which suffer acid-catalysed hydrolysis via a rapid pre-equilibrium protonation of the substrate followed by rate-limiting attack of the nucleophile to effect denitrosation or amidine hydrolysis.The present results are interpreted in terms of a protonation of the imidazoline nitroso nitrogen of N-nitrosoclonidine which results in an intermediate that decomposes by loss of the nitroso group.
- Iley, Jim,Norberto, Fatima,Rosa, Eduarda,Cardoso, Victor,Rocha, Carlos
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p. 591 - 594
(2007/10/02)
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- Feed additive for improving growth in agricultural animals
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By using α-mimetics, particularly compounds of general formulae I to III and the compounds listed in Table I, as feed additives in fattening animals, it has surprisingly been possible to improve the daily weight gain, the utilisation of fodder and the ratio of muscle to fat in favor of the proportion of muscle and protein.
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- A Novel Synthesis of Clonidine, an Anti-Hypertensive Drug from o-Chloronitrobenzene
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An elegant, cost-effective synthesis of clonidine (4) is reported from readily available starting materials. o-Chlorophenylhydroxylamine (2), obtained from o-chloronitrobenzene, is formylated to N-(2-chlorophenyl)-N-hydroxyformamide (3).In a one-pot procedure, 3 is converted to clonidine by chlorination with thionyl chloride and then with thionyl chloride/sulfuryl chloride, followed by condensation with ethylenediamine.
- Ayyangar, N. R.,Brahme, K. C.,Srinivasan, K. V.
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- Method of preparing 2-(phenylamino)-imidazolines-(2)
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A process for preparing compounds of the formula: STR1 or pharmaceutically acceptable salts thereof, wherein R1 and R2 each individually are hydrogen, halogen, or nitro, which comprises the steps of: (a) alkylating a compound of the formula: STR2 wherein R3 is C1 to C4 alkyl or phenyl, with a compound of the formula: wherein R4 is C1 to C6 alkyl or phenyl-alkyl where the alkyl is C1 to C4 and X is halogen, in the presence of a base to yield a compound of the formula: STR3 and; (b) cyclizing the compound formed during step (a) with ethylenediamine mono-p-toluenesulphonate at a temperature of 100° to 200° C. to yield the desired product. New intermediate compounds are also disclosed. The desired products have antihypertensive properties.
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- 2-Imino-imidazolidine derivatives
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2-Imino-imidazolidine derivatives of the formula STR1 wherein R1, R2, R3 and R4 are as hereinafter set forth, and pharmaceutically acceptable acid addition salts thereof, are described. The 2-imino-imidazolidine derivatives are useful in the treatment of hypertension.
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- Imidazoline derivatives and the preparation thereof
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A process for the preparation of 2-(substituted aryl)amino-2-imidazoline derivatives by reacting appropriate substituted aniline derivatives with 1-aroyl-imidazoline-2-ones in the presence of at least two mols of phosphorus oxychloride per mol of the aniline derivative and optionally hydrolyzing the resulting intermediate compound. Certain novel 2-dihaloarylamino-2-imidazoline derivatives with hypotensive action are also disclosed.
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- Process for the manufacture of 2-arylamino-2-imidazoline derivatives and their salts
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A process for the preparation of the known and valuable 2-aryl-amino-2-imidazoline derivatives which comprises condensing an appropriately substituted aniline with a 1-acyl-imidazolidin-2-one to produce an intermediate compound which on neutralisation in an aqueous medium is converted into a N-acyl derivative of the 2-aryl-amino-2-imidazoline, and splitting the intermediate compound or the said N-acyl derivative to give the corresponding free arylamino-2-imidazoline derivative or a salt thereof.
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