Principais métodos de síntese de amidinas

Santos, Maurício Silva dos; Bernardino, Alice M. R.; Souza, Marcos C. de

doi:10.1590/s0100-40422006000600027

Cited by 8 publications

(2 citation statements)

References 44 publications

(46 reference statements)

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“…Regarding SAXA degradation process, reactions (Equations (10)–(12)) were constructed, based on specific available literature [16,30,31], amidine, epimer, and formyl amide formation mechanisms [19,32,33,34,35,36,37] and own experimental measurements. Jones et al identified solvent’s propensity to participate in proton transfer and ESCA autocatalysis as the two main contributors of SAXA to ESCA conversion [16]; however, to our set of solid-state reactions, this does not directly apply, owing to slower reaction rates and specific micro-environmental conditions, established by tablet excipients.…”

Section: Resultsmentioning

confidence: 99%

Understanding and Kinetic Modeling of Complex Degradation Pathways in the Solid Dosage Form: The Case of Saxagliptin

et al. 2019

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Drug substance degradation kinetics in solid dosage forms is rarely mechanistically modeled due to several potential micro-environmental and manufacturing related effects that need to be integrated into rate laws. The aim of our work was to construct a model capable of predicting individual degradation product concentrations, taking into account also formulation composition parameters. A comprehensive study was done on active film-coated tablets, manufactured by layering of the drug substance, a primary amine compound saxagliptin, onto inert tablet cores. Formulation variables like polyethylene glycol (PEG) 6000 amount and film-coat polymer composition are incorporated into the model, and are connected to saxagliptin degradation, via formation of reactive impurities. Derived reaction equations are based on mechanisms supported by ab initio calculations of individual reaction activation energies. Alongside temperature, relative humidity, and reactant concentration, the drug substance impurity profile is dependent on micro-environmental pH, altered by formation of acidic PEG degradation products. A consequence of pH lowering, due to formation of formic acid, is lower formation of main saxagliptin degradation product epi-cyclic amidine, a better resistance of formulation to high relative humidity conditions, and satisfactory tablet appearance. Discovered insights enhance the understanding of degradational behavior of similarly composed solid dosage forms on overall drug product quality and may be adopted by pharmaceutical scientists for the design of a stable formulation.

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Section: Resultsmentioning

confidence: 99%

Understanding and Kinetic Modeling of Complex Degradation Pathways in the Solid Dosage Form: The Case of Saxagliptin

et al. 2019

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“…Although the significant number of synthetic routes into discrete amidines have been reviewed elsewhere , amidine‐based isologs of Arg have been prepared as discrete compounds through a variety of different means, including various iterations of standard Pinner syntheses of nitrile substrates , condensation of alkyl acetimidates with the δ‐amine of appropriately functionalized Orn precursors , and treatment of Orn δ‐thioamides with ammonia . Overwhelmingly, the final product in these syntheses has been the discrete Arg isologs themselves, without their incorporation into larger peptides.…”

Section: Introductionmentioning

confidence: 99%

On‐resin synthesis of novel arginine‐isostere peptides bearing substituted amidine headgroups

Flemer

Madalengoitia

2011

Journal of Peptide Science

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A methodology is presented for the facile synthesis of Arg-containing peptides modified at the guanidine headgroup as substituted amidine cores. This process allows for the iterative construction of these Arg isosteres while the peptide is being built out on the solid support, providing a high potential for diversity in substitution pattern in the resulting peptide. A series of N-Pmc-substituted thioamides were condensed with deprotected δ-N Orn-bearing peptides while attached to the solid support using Mukaiyama's reagent as coupling reagent, yielding isosteric Arg-containing analogs. Peptides were cleaved using trimethylsilyl trifluoromethanesulfonate/TFA and analyzed in their crude form in order to illustrate the amenability of this process toward production of peptide isolates in high crude purity. Arg-containing peptides having a single Arg isostere were utilized to show the general utility of this approach as well as a multiple-Arg-containing construct, illustrating the amenability of this method toward stepwise construction of differently substituted amidine headgroups within the same peptide.

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Catalytic Synthesis of 1,2,4,5‐Tetrasubstituted 1H‐Imidazole Derivatives: State of the Art

et al. 2019

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1,2,4,5-Tetrasubstituted-1H-imidazoles are a large family of heteroarene derivatives that are known to include natural products isolated from marine sponges and synthetic compounds possessing a broad range of biological and pharmacological properties. Consequently, a great deal of attention has been given to the synthesis of these heteroarenes and reviews covering some synthetic aspects of this topic have been published in recent years. However, none of these reviews provides a comprehensive overview of the several catalytic methods developed in the literature for the preparation of this important class of heteroarenes. This article review with 469 references, 63% of them being related to the period 2010-2017, aims to provide an updated critical picture of the catalytic processes reported in the literature up to the end of 2017 for the synthesis of 1,2,4,5-tetrasubstituted-1H-imidazoles illustrating these protocols and their characteristic features such as scope, efficiency, versatility, and limitations. The review also summarizes the mechanisms of the catalytic processes proposed for many of the reported processes.

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Principais métodos de síntese de amidinas

Cited by 8 publications

References 44 publications

Understanding and Kinetic Modeling of Complex Degradation Pathways in the Solid Dosage Form: The Case of Saxagliptin

Understanding and Kinetic Modeling of Complex Degradation Pathways in the Solid Dosage Form: The Case of Saxagliptin

On‐resin synthesis of novel arginine‐isostere peptides bearing substituted amidine headgroups

Catalytic Synthesis of 1,2,4,5‐Tetrasubstituted 1H‐Imidazole Derivatives: State of the Art

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