- Mechanistic Understanding of a Robust and Scalable Synthesis of Per(6-deoxy-6-halo)cyclodextrins, Versatile Intermediates for Cyclodextrin Modification
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Cyclodextrin (CD) perfunctionalization reactions are challenging to study because they proceed through a number of regioisomeric intermediates, thus warranting creative approaches to understanding the reaction mechanism. Particularly useful perfunctionalization targets are per(6-deoxy-6-halo)cyclodextrins. Their standard synthesis entails selective SN2 halogenation at their primary alcohols using a Vilsmeier reagent, but this requires a strongly basic quench to unmask the Vilsmeier-capped secondary alcohols. Herein we present an alternative and simple acidic hydrolytic quench that utilizes existing HX in the end-of-reaction solution and requires only the addition of water. We performed a detailed mechanistic investigation of the new quench, and a central feature was the use of proton sponge to develop an 1H NMR titration method for HX in organic solvent. This method was used to both quantify and remove HX in the prequenched reaction solution. The HX-free prequenched solution enabled us to (1) identify sensitive intermediates during the quench, (2) quantify all of the reaction byproducts, and (3) determine that HX is critical for hydrolysis. We then studied the halogenation reaction, wherein the new acidic quench facilitated high-throughput experimentation, using mass spectrometry as well as Design of Experiments with automated reaction profiling. Through this, we were able to establish robustness and understand the complex effects of Vilsmeier equivalents and temperature on the reaction outcome.
- Zultanski, Susan L.,Kuhl, Nadine,Zhong, Wendy,Cohen, Ryan D.,Reibarkh, Mikhail,Jurica, Jon,Kim, Jungchul,Weisel, Lauren,Ekkati, Anil R.,Klapars, Artis,Gauthier, Donald R.,McCabe Dunn, Jamie M.
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supporting information
p. 597 - 607
(2020/10/12)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF SUGAMMADEX SODIUM AND ITS NOVEL POLYMORPHIC FORM
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The present invention provides an improved process for the preparation of Sugammadex sodium of formula (I) having more than 98.5% purity along with less than 1.0% monohydroxy Sugammadex sodium and less than 0.15% any other known or unknown impurities by HPLC.
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Page/Page column 25
(2020/04/25)
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- METHOD FOR PREPARATION OF SUGAMMADEX SODIUM
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The present invention provides a method for improved preparation of Sugammadex sodium.
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Paragraph 0035
(2019/03/08)
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- PROCESS FOR MAKING SUGAMMADEX
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The invention deals with a novel process for making intermediates of the pharmaceutically useful product Sugammadex of formula (1).
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Page/Page column 11; 12; 13
(2019/01/16)
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- POLYMORPHS OF SUGAMMADEX AND PROCESS FOR PREPARATION OF SUGAMMADEX
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The present invention provides a crystalline form of Suagmmadex sodium, characterized by an X-ray powder diffraction pattern. The present invention further provides crystalline forms of Suagmmadex sodium for use in the manufacture of a pharmaceutical composition or a medicament. The present invention further provides a pharmaceutical composition comprising the crystalline form of Sugammadex sodium of the present invention and at least one pharmaceutical acceptable excipient.
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Paragraph 0026-0027
(2019/03/08)
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- PROCESSES FOR THE PREPARATION OF SUGAMMADEX
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The present invention provides processes for the preparation of sugammadex: (I) In one aspect, there is provided a process for the preparation of sugammadex from 8-per-deoxy-8-bromo-γ-cyclodextrin and 3-mercaptopropionic acid. In another aspect, there is provided an alternative process for the preparation of sugammadex from 8-per-deoxy-8-bromo-γ-cyclodextrin and disodium 3-mercaptopropionate. In another aspect, there is provided a process for the preparation of 8-per-deoxy-8-bromo-γ-cyclodextrin, which may be used in the production of sugammadex. In one such aspect, there is provided a process for the preparation of 8-per-deoxy-8-bromo-γ-cyclodextrin from γ-cyclodextrin and a brominating agent. In another such aspect, there is provided a process for the preparation of 8-per-deoxy-8-bromo-γ-cyclodextrin comprising, inter alia, reacting γ-cyclodextrin with an electrophilic brominating agent, a deoxygenating agent, and an acid in the presence of an organic solvent.
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Page/Page column 23; 24
(2019/12/28)
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- PROCESS FOR MAKING SUGAMMADEX
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The invention relates to a novel process for making the pharmaceutical product Sugammadex. OVERVIEW OF THE PRIOR ART Sugammadex, i.e. 5-Cyclooctakis-(1→4)- [6-S-(2-carboxyethyl)-6-thio-alfa-D-glucopyranosyl] of formula (I), is a modified γ-cyclodextrin. Sugammadex is the first selective relaxant binding agent for reversal of neuromuscular blockade by the agent rocuronium or vecuronium in general anesthesia. It was approved in 2008
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Page/Page column 13; 14
(2017/09/09)
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- Efficient mechanochemical synthesis of regioselective persubstituted cyclodextrins
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A number of per-6-substituted cyclodextrin derivative syntheses have been effectively carried out in a planetary ball mill under solvent-free conditions. The preparation of Bridion and important per-6-amino/thiocyclodextrin intermediates without polar aprotic solvents, a source of byproducts and persistent impurities, could be performed. Isolation and purification processes could also be simplified. Considerably lower alkylthiol/halide ratio were necessary to reach the complete reaction in comparison with thiourea or azide reactions. While the presented mechanochemical syntheses were carried out on the millimolar scale, they are easily scalable.
- Jicsinszky, Laszlo,Caporaso, Marina,Martina, Katia,Gaudino, Emanuela Calcio,Cravotto, Giancarlo
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supporting information
p. 2364 - 2371
(2016/12/07)
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- A convenient procedure for the formation of per(6-deoxy-6-halo) cyclodextrins using the combination of tetraethylammonium halide with [Et 2NSF2]BF4
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A convenient and efficient procedure for the regioselective halogenation of the primary alcohols of cyclodextrins using the reagent combination of tetraethylammonium halide with [Et2NSF2]BF4 is described. Georg Thieme Verlag Stuttgart New York.
- Liu, Xiaofeng,Cheng, Sen,Wang, Xiaolei,Xue, Weihua
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p. 3103 - 3105
(2013/12/04)
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- An improved and alternative method for the preparation of per(6-bromo-6-deoxy)cyclodextrins
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A practical and efficient approach to the regioselective synthesis of per(6-bromo-6-deoxy)cyclodextrins is described. The method utilizes the easily accessible (chloro(phenylthio)methylene)dimethylammonium chloride (CPMA), circumventing disadvantages of earlier protocols. Georg Thieme Verlag Stuttgart. New York.
- Xue, Weihua,Zhang, Lifen
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experimental part
p. 3612 - 3614
(2011/12/16)
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- Novel polycarboxylated EDTA-type cyclodextrins as ligands for lanthanide binding: Study of their luminescence, relaxivity properties of Gd(iii) complexes, and PM3 theoretical calculations
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Novel EDTA-type cyclodextrin (CD) derivatives, AEDTA, BEDTA and GEDTA, bearing 6, 7 and 8 bis(carboxymethyl)amino (iminodiacetic acid) groups, respectively, were prepared, and their complexation with Eu(iii), Tb(iii) and Gd(iii) ions was studied. Luminescence titrations and mass spectrometry showed formation of multimetal complexes (AEDTA 2 to 3, BEDTA mainly 3 and GEDTA exactly 4 metal ions), whereas luminescence lifetime measurements revealed the presence of exchangeable water molecules. Semiempirical quantum mechanical calculations, performed by the PM3 method and assessed by DFT calculations on model ligands, indicated efficient multi-metal complexation, in agreement with the experiment. The structures showed coordination of the metal ions in the outer primary side of the CDs via 4 carboxylate O atoms, 2 N atoms and a glucopyranose O atom per metal ion. Coordination of water molecules was also predicted, in accordance with experimental results. Calculated bond lengths and angles were in agreement with literature experimental values of lanthanide complexes. Calculated energies showed that complex stability decreases in the order GEDTA > BEDTA > AEDTA. 1H NMR molecular relaxivity measurements for the Gd(iii) complexes of AEDTA, BEDTA or GEDTA in water afforded values 4 to 10 times higher than the relaxivity of a commercial contrast agent at 12 MHz, and 6 to 20 times higher at 100 MHz. Solutions of BEDTA and GEDTA Gd(iii) complexes in human blood plasma displayed relaxivity values at 100 MHz 7 and 12 times, respectively, higher than the commercial agent. MTT tests of the Gd(iii) complexes using human skin fibroblasts did not show toxicity. Attempts to supramolecularly sensitize the luminescence of the lanthanide complexes using various aromatic CD guests were ineffective, evidently due to large guest-metal distances and inefficient inclusion. The described lanthanide complexes, could be useful as contrast agents in MRI.
- Maffeo, Davide,Lampropoulou, Maria,Fardis, Michael,Lazarou, Yannis G.,Mavridis, Irene M.,Mavridou, Despoina A. I.,Urso, Elena,Pratsinis, Harris,Kletsas, Dimitris,Yannakopoulou, Konstantina
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scheme or table
p. 1910 - 1921
(2010/08/20)
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- Synthesis, characterization, and remarkable biological properties of cyclodextrins bearing gnanidinoalkylamino and aminoalkylamino groups on their primary side
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The introduction of aminoalkylamino and guanidinoalkylamino substituents on the primary side of β-and γ-cyclodextrin (CDs) resulted in a series of novel compounds that were extensively characterized by NMR spectroscopy and mass spectrometry. Bromination of the primary side of β-and γ-CD, and reaction with neat alkylene diamines at a pressure of 7 atm afforded aminoalkylamino derivatives that were then guanylated at the primary amino group to give the corresponding guanidinoalkylamino-CDs. These compounds are water soluble and display pKa values that allow them to be mostly protonated at neutral pH; for example, pKa1-6.4 and pK a2-9.5 for the aminoethylamino-β-CD and pKa1-7.8 and pKa2-11.0 for the guanidinoethylamino-β-CD. The title CDs are rigid, cyclic α-D-glucopyranose oligomers (heptamers or octamers) with branches that resemble lysine and arginine side chains that enable multiple interactions with suitable substrates. Thus, they bear similarities to known cell-penetrating peptides. Indeed, the compounds were found to cross the membranes of HeLa cells and penetrate inside the cytoplasm quickly, the guadinylated ones within 15 min, as shown by fluorescence microscopy using fluorescein-labeled derivatives. The toxicity of the compounds, measured by performing MTT tests, ranged from 50 to 300 μM. Furthermore, some of the aminated CDs could facilitate the transfection of DNA expressing the green fluorescent protein (GFP) in HEK 293T cells, with effectiveness comparable to the commercial agent Lipofectamine 2000. Circular dichroism, atomic force microscopy and electrophoresis experiments confirmed the strong interaction of the compounds with DNA. Because of their carbohydrate, non-peptide nature the title compounds are not anticipated to be enzymatically labile or immunogenic, and thus they fulfill many of the criteria for non-hazardous transport vectors in biological and pharmaceutical applications.
- Mourtzis, Nikolaos,Paravatou, Maria,Mavridis, Irene M.,Roberts, Michael L.,Yannakopoulou, Konstantina
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scheme or table
p. 4188 - 4200
(2009/05/07)
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- Per(6-guanidino-6-deoxy)cyclodextrins: Synthesis, characterisation and binding behaviour toward selected small molecules and DNA
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Per(6-guanidino-6-deoxy)-cyclodextrins 4a, 4b and 4c are novel derivatives, resulting from homogeneous introduction of the guanidino group at the primary side of α-, β- and γ-cyclodextrins. The products were obtained from the corresponding amino derivatives, as direct guanidinylation of the known bromo-cyclodextrins provided mixtures. The new compounds were fully characterized by NMR spectroscopy and other analytical methods, and their interaction with guest molecules was studied. Strong complexation with 4-nitrophenyl phosphate (NPP) disodium salt was observed (Kbinding ~5 × 104 M-1), whereas the non-phosphorylated substrate nitrobenzene (NB) formed a very weak complex. 2D ROESY spectra revealed cavity inclusion in both cases, however the orientation of NPP was opposite to that of NB, such that the phosphate group is oriented toward the primary side facing the guanidine groups. The strong affinity of 4 towards the phosphorylated guest suggested that interaction with DNA was possible. The new compounds were found to completely inhibit the migration of ultra pure calf thymus DNA during agarose gel electrophoresis, whereas no effects were observed with guanidine alone or with the plain cyclodextrins. Further, the condensation of DNA into nanoparticles in the presence of 4b was demonstrated by atomic force microscopy, confirming strong electrostatic interaction between the biopolymer and the multicationic products 4. The strong guanidine-phosphate interactions between 4 and DNA were therefore attributed to the clustering of the guanidine groups in the primary area of the cyclodextrin. Cavity effects could not be assessed. This journal is The Royal Society of Chemistry.
- Mourtzis, Nikolaos,Eliadou, Kyriaki,Aggelidou, Chrysie,Sophianopoulou, Vassiliki,Mavridis, Irene M.,Yannakopoulou, Konstantina
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p. 125 - 131
(2008/03/14)
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- Bilayer vesicles of amphiphilic cyclodextrins: Host membranes that recognize guest molecules
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A family of amphiphilic cyclodextrins (6, 7) has been prepared through 6-S-alkylation (alkyl=n-dodecyl and n-hexadecyl) of the primary side and 2-O-PEGylation of the secondary side of α-, β-, and γ-cyclodextrins (PEG = poly(ethylene glycol)). These cyclodextrins form nonionic bilayer vesicles in aqueous solution. The bilayer vesicles were characterized by transmission electron microscopy, dynamic light scattering, dye encapsulation, and capillary electrophoresis. The molecular packing of the amphiphilic cyclodextrins was investigated by using small-angle X-ray diffraction of bilayers deposited on glass and pressure-area isotherms obtained from Langmuir monolayers on the air-water interface. The bilayer thickness is dependent on the chain length, whereas the average molecular surface area scales with the cyclodextrin ring size. The alkyl chains of the cyclodextrins in the bilayer are deeply interdigitated. Molecular recognition of a hydrophobic anion (adamantane carboxylate) by the cyclodextrin vesicles was investigated by using capillary electrophoresis, thereby exploiting the increase in electrophoretic mobility that occurs when the hydrophobic anions bind to the nonionic cyclodextrin vesicles. It was found that in spite of the presence of oligo(ethylene glycol) substituents, the β-cyclodextrin vesicles retain their characteristic affinity for adamantane carboxylate (association constant Ka = 7.1 × 103M-1), whereas γ-cyclodextrin vesicles have less affinity (Ka = 3.2 × 103M-1), and α-cyclodextrin or non-cyclodextrin, nonionic vesicles have very little affinity (Ka ≈100M -1). Specific binding of the adamantane carboxylate to β-cyclodextrin vesicles was also evident in competition experiments with β-cyclodextrin in solution. Hence, the cyclodextrin vesicles can function as host bilayer membranes that recognize small guest molecules by specific non-covalent interaction.
- Falvey, Patrick,Lim, Choon Woo,Darcy, Raphael,Revermann, Tobias,Karst, Uwe,Giesbers, Marcel,Marcelis, Antonius T. M.,Lazar, Adina,Coleman, Anthony W.,Reinhoudt, David N.,Ravoo, Bart Jan
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p. 1171 - 1180
(2007/10/03)
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- An improved synthesis of 6-deoxyhalo cyclodextrins via halomethylenemorpholinium halides Vilsmeier-Haack Type reagents
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Per(6-bromo-6-deoxy)cyclomalto-hexaose, -heptaose, and -octaose and the corresponding per(6-chloro-6-deoxy) derivatives were prepared in high yield by reaction of bromomethylenemorpholinium bromide or chloromethylenemorpholinium chloride, respectively, with cyclomaltohexaose, cyclomaltoheptaose and cyclomaltooctaose in dimethylformamide.
- Chmurski, Kazimierz,Defaye, Jacques
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p. 7365 - 7368
(2007/10/03)
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- Synthesis of monofacially functionalized cyclodextrins bearing amino pendent groups
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Derivatives of the cyclodextrins, αCD, βCD, and ΥCD, in which all primary hydroxyls are substituted by amine pendant groups, may be synthesized efficiently from the per-6-bromo-6-deoxy-CD derivatives by direct reaction with amines. These ACD derivatives, which bear six, seven, or eight amine pendent groups, represent interesting biomimetic receptors and catalysts. The synthetic strategy relies on quantitative transformation and efficient purification as is demonstrated by preparation of 11 homogeneous ACD derivatives. The limitations of the synthesis and potential adaptations are illustrated by the synthesis of several more ACD derivatives to >95% purity. A synthetic route to a CD persubstituted with primary amine functionalities at the primary face, per-6-bromo-6-deoxy-CD, yields an alternative reagent to the simple per-6-bromo-6-deoxy-CD, which is more suitable for further synthetic transformations. The synthetic strategy is further adapted to preparation of a prototypical (6 + 1)-ACD derivative in which one primary position is substituted with a sulfide group and the remaining six primary face positions are substituted with amine pendent groups.
- Vizitiu, Dragos,Walkinshaw, Caroline S.,Gorin, Borio I.,Thatcher, Gregory R. J.
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p. 8760 - 8766
(2007/10/03)
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- Direct synthesis of amphiphilic α-, β-, and γ-cyclodextrins
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The clean one step synthesis of the amphiphilic α-, β-, and γ-cyclodextrins starting from per-(6-bromo-6-deoxy)-α-, -β-, and -γ-cyclodextrins is described. The role of the lipophilic tail is played by various aryl groups (phenyl, p-bromophenyl, p-O-butoxyphenyl, p-pentylphenyl, and o-, m-, and p-nitrophenyl) linked by a thioether bridge to the position C-6 of each glucopyranose unit. The yields of the S-alkylation reactions were very high (85-95%).
- Chmurski, Kazimierz,Coleman, Antony W.,Jurczak, Janusz
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p. 787 - 796
(2007/10/03)
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- Efficient perfacial derivatization of cyclodextrins at the primary face
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Synthesis of thirteen cyclodextrin (CD) derivatives via the per-6-bromo-6-deoxy-CD is reported in order to demonstrate the efficiency and ease of perfacial functionalization of α, β and γCD employing a Vilsmeier-Haack reagent.
- Gorin, Boris I.,Riopelle, Richard J.,Thatcher, Gregory R. J.
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p. 4647 - 4650
(2007/10/03)
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