RESUMEN
A stereoselective aza-Henry reaction between an arylnitromethane and Boc-protected aryl aldimine using a homogeneous Brønsted acid-base catalyst was translated from batch format to an automated intermittent-flow process. This work demonstrates the advantages of a novel intermittent-flow setup with product crystallization and slow reagent addition which is not amenable to the standard continuous equipment: plug flow tube reactor (PFR) or continuous stirred tank reactor (CSTR). A significant benefit of this strategy was the integration of an organocatalytic enantioselective reaction with straightforward product separation, including recycle of the catalyst, resulting in increased intensity of the process by maintaining high catalyst concentration in the reactor. A continuous campaign confirmed that these conditions could effectively provide high throughput of material using an automated system while maintaining high selectivity, thereby addressing nitroalkane safety and minimizing catalyst usage.
RESUMEN
The delamination of glass contact surfaces because of hydrolytic instability has been well documented. However, the lack of glass surface integrity can also lead to other undesirable outcomes prior to visible glass delamination. This work shows how the early stages of delamination, namely, glass corrosion, can influence the chemical stability of active pharmaceutical ingredient (API) solutions contained within a glass container, even prior to the observation of visible delamination. Multiple containers, all constructed of glass classified as USP Type I, were evaluated for hydrolytic stability and how they influence the chemical stability of the API in question. The glass composition of these analytical consumables, the vendor source, and presumably manufacturing process were examined. The implications of glass container durability on product development decisions, the influence on analytical results, and the practice of like-for-like glass container interchangeability are considered.
Asunto(s)
Embalaje de Medicamentos/métodos , Estabilidad de Medicamentos , Vidrio/química , Corrosión , Almacenaje de MedicamentosRESUMEN
Mitosis inhibitor (R)-litronesib (LY2523355) is a 1,3,4-thiadiazoline-bearing phenyl and N-(2-ethylamino)ethanesulfonamido-methyl substituents on tetrahedral C5. Chiral instability has been observed at pH 6 and above with the rate of racemization increasing with pH. A positively charged trigonal intermediate is inferred from the fact that p-methoxy substituent on the phenyl accelerated racemization, whereas a p-trifluoromethyl substituent had the opposite effect. Racemization is proposed to occur through a relay mechanism involving intramolecular deprotonation of the sulfonamide by the side chain amino group and attack of the sulfonamide anion on C5, cleaving the C5S bond, to form an aziridine; heterolytic dissociation of the aziridine yields an ylide. This pathway is supported by (1) a crystal structure providing evidence for a hydrogen bond between the sulfonamide NH and the amino group, (2) effects of substituents on the rate of racemization, and (3) computational studies. This racemization mechanism results from neighboring group effects in this densely functionalized molecule. Of particular novelty is the involvement of the side-chain secondary amino group, which overcomes the weak acidity of the sulfonamide by anchimeric assistance.
Asunto(s)
Carbono/química , Soluciones/química , Sulfonamidas/química , Tiadiazoles/química , Agua/química , Aziridinas/química , Catálisis , Estabilidad de Medicamentos , Enlace de Hidrógeno , Concentración de Iones de Hidrógeno , Cinética , Estructura Molecular , EstereoisomerismoRESUMEN
Oxidative susceptibility testing was performed on a drug substance containing a methoxy-naphthalene moiety. 2,2'-azobisisobutyronitrile (AIBN) was employed to initiate peroxy radical oxidation to mimic autoxidation processes. In acetonitrile (ACN)-water solvents, three major degradation products are formed. However, addition of small amounts of methanol to the solvent system completely eliminated the observed degradation products. To understand this effect, the structures of the three degradants have been elucidated using nuclear magnetic resonance, liquid chromatography-tandem mass spectrometry, and accurate mass Fourier transform ion cyclotron resonance mass spectrometry. One degradant structure definitively proves the degradation resulted from alkoxy radicals (2-cyano-2 propoxy radical) arising from the disproportionation of the tertiary AIBN-derived peroxy radicals, rather than from the intended action of the AIBN peroxy radicals themselves. The reaction occurs over a wide range of AIBN and drug substance concentrations. This "protective effect" of several percent methanol by volume is rationalized by known methanol H atom donation rates to similar tert-butoxy and cumyloxy radicals (ca. 10 M(-1) s(-1) ) and the high methanol concentration relative to the dilute substrate being investigated. This work confirms recent proposals for addition of at least about 10% methanol to the standard ACN-water AIBN stress testing diluent to insure that only the desired peroxy radical activity is present during the oxidative stress test.
Asunto(s)
Acetonitrilos/química , Radicales Libres/química , Metanol/química , Nitrilos/química , Agua/química , Oxidación-Reducción , Peróxidos/química , Solventes/químicaRESUMEN
A mass spectrometric method was developed for the screening of the amido functionality in monofunctional protonated analytes. This method is based on selective gas-phase derivatization of protonated analytes by (N,N-diethylamino)dimethylborane in a Fourier transform ion cyclotron resonance (FT-ICR) and triple quadrupole mass spectrometer. Examination of a series of protonated analytes demonstrated that only the compounds containing the amido functionality react with the aminoborane by the derivatization reaction. The mechanism involves proton transfer from the protonated analyte to the borane, followed by addition of the amide to the boron center, which leads to the elimination of neutral diethylamine. The derivatized analytes are readily identified on the basis of a shift of 40 m/z units relative to the m/z value of the protonated analyte and characteristic boron isotope patterns. Collision-activated dissociation was used to provide support for the structures assigned to the derivatized analytes. The structural information gained from this gas-phase derivatization method will aid in the functional group identification of unknown compounds and their mixtures.
Asunto(s)
Amidas/análisis , Compuestos Orgánicos/análisis , Compuestos Orgánicos/química , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Amidas/química , Aminas/análisis , Aminas/química , Boranos/análisis , Boranos/química , Química Orgánica/métodos , Iones , Oxígeno/química , Protones , Espectroscopía Infrarroja por Transformada de Fourier/instrumentaciónRESUMEN
A mass spectrometry method is presented for the identification of compounds that contain the primary N-oxide functional group. This method utilizes a gas-phase ion-molecule reaction with dimethyl disulfide that rapidly and selectively derivatizes the protonated primary N-oxide functional group in a mass spectrometer to yield an ionic reaction product (with 31 Da higher mass than that of the protonated molecule) that is diagnostic for the presence of a primary N-oxide functionality. A variety of protonated analytes containing different functional groups were tested in Fourier transform ion-cyclotron resonance and triple quadrupole mass spectrometers to probe the selectivity of the reaction. Only molecules containing the protonated primary N-oxide functional group yielded the diagnostic reaction product; all other protonated molecules gave protonated dimethyl disulfide or no reaction products. The feasibility of this method for compound screening was tested by examining six analytes with the same molecular formula but different atom connectivity. The one analyte that contained the primary N-oxide functional group was readily differentiated from the other analytes.
Asunto(s)
Iones/química , Espectrometría de Masas/métodos , Óxidos/análisis , Óxidos/química , Estructura Molecular , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
A mass spectrometric method is described for the identification and counting of hydroxyl groups in an analyte. Analytes introduced into a FT-ICR mass spectrometer and ionized by positive mode ESI were allowed to react with the neutral reagent diethylmethoxyborane. This results in derivatization of the hydroxyl groups of the analytes by replacement of a proton with a diethylborenium ion. Protonated polyols react by consecutive derivatization reactions, wherein all, or nearly all, of the hydroxyls are derivatized. The polyol derivatization products are separated by 68 mass units in the mass spectrum. This 68 Da mass shift, along with 30 Da mass shifts arising from intramolecular derivatization of the primary derivatization products, makes it easy to count the number of functional groups present in the analyte. The utility of this method for the analysis of polyols as single-component solutions, as mixtures, or in HPLC effluent (LC-MS analysis) is demonstrated.
Asunto(s)
Compuestos de Boro/química , Iones/química , Espectrometría de Masa por Ionización de Electrospray/métodos , Alcoholes del Azúcar/análisis , Cromatografía Líquida de Alta Presión , Ciclotrones , Eritritol/análisis , Eritritol/química , Análisis de Fourier , Manitol/análisis , Manitol/química , Reproducibilidad de los Resultados , Alcoholes del Azúcar/química , Xilitol/análisis , Xilitol/químicaRESUMEN
Protonated oxygen-containing monofunctional compounds react with selected methoxyborane reagents by proton transfer followed by nucleophilic substitution of methanol at the boron atom in a Fourier transform ion cyclotron resonance mass spectrometer. The derivatized oxygen functionality can be identified by H/D exchange, collision-activated dissociation, or both. This information on the identity of the functionalities in the analyte, in conjunction with molecular formula information obtained from exact mass measurements on either the protonated or derivatized analyte, facilitates structure elucidation of unknown organic compounds in a mass spectrometer.