RESUMEN
Novel treatment routes are emerging for an array of diseases and afflictions. Complex dosage forms, based on active pharmaceutical ingredients (APIs) with previously undesirable physicochemical characteristics, are becoming mainstream and actively pursued in various pipeline initiatives. To fundamentally understand how constituents in these dosage forms interact on a molecular level, analytical methods need to be developed that encompass selectivity and sensitivity requirements previously reserved for a myriad of in vitro techniques. The knowledge of precise chemical interactions between drugs and excipients in a dosage form can streamline formulation development and process screening capabilities through the identification of properties that influence rates and mechanisms of drug release in a cost-effective manner, relative to long-term in vivo studies. Through this work, a noncompendial in vitro release (IVR) method was developed that distinguished the presence of individual components in a complex crystalline nanosuspension environment. Doravirine was formulated as a series of long-acting injectable nanosuspensions with assorted excipients, using low- and high-energy wet media milling methods. IVR behavior of all formulation components were monitored using a robust continuous flow-through (CFT) dissolution setup (USP-4 apparatus) with on-line 1H NMR end-analysis (flow-NMR). Results from this investigation led to a better understanding of formulation parameter influences on nanosuspension stability, surface chemistry, and dissolution behavior. Flow-NMR can be applied to a broad range of dosage forms in which specific molecular interactions from the solution microenvironment require further insight to enhance product development capabilities.
Asunto(s)
Composición de Medicamentos/métodos , Liberación de Fármacos , Inyecciones , Espectroscopía de Resonancia Magnética/métodos , Nanopartículas/administración & dosificación , Suspensiones/administración & dosificación , Suspensiones/farmacocinética , Química Farmacéutica/instrumentación , Estabilidad de Medicamentos , Excipientes/química , Técnicas In Vitro/métodos , Nanopartículas/química , Tamaño de la Partícula , Piridonas/química , Solubilidad , Triazoles/químicaRESUMEN
Tritium-labeled molecules are critical tools for elucidating the binding and metabolic properties of bioactive compounds, particularly during pharmaceutical discovery. Direct tritiation of inert C-H bonds with T2 gas is an ideal approach for tritium labeling, but significant gaps remain for direct tritiation of structurally complex molecules with diverse functional groups. Here we report the first application of palladium(II) C-H activation chemistry for tritiation with T2 gas. This practical transformation exhibits novel substrate scope and greater functional group tolerance compared to previous state of the art tritiation methods, and has been applied to directly tritiate 9 complex pharmaceuticals and an unprotected dipeptide. The isolated tritium-labeled products exhibit >15â Ci mmol-1 specific activity, exceeding the typical requirements for application in studies of molecular interaction and metabolism.
Asunto(s)
Paladio/química , Radiofármacos/química , Carbono/química , Catálisis , Hidrógeno/química , Marcaje Isotópico , Radiofármacos/síntesis química , Tritio/químicaRESUMEN
A highly efficient asymmetric synthesis of the key tetrahydropyranol intermediate of DPP-4 inhibitor omarigliptin (1) is described. The successful development of a protecting-group- and precious-metal-free synthesis was achieved via the discovery of a practical asymmetric Henry reaction and the application of a one-pot nitro-Michael-lactolization-dehydration through-process. Other features of the synthesis include a highly efficient MsCl-mediated dehydration and a crystallization-induced dynamic resolution for exceptional ee and dr upgrade. The synthesis of this complex intermediate utilizes simple starting materials and proceeds in four linear steps.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Piranos/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/química , Compuestos Heterocíclicos con 2 Anillos/química , Estructura Molecular , Piranos/químicaRESUMEN
Compounds containing tritium are widely used across the drug discovery and development landscape. These materials are widely utilized because they can be efficiently synthesized and produced at high specific activity. Results from internally calibrated (3)H and (1)H nuclear magnetic resonance (NMR) spectroscopy suggests that at least in some cases, this calibrated approach could supplement or potentially replace radio-high-performance liquid chromatography for radiochemical purity, dilution and scintillation counting for the measurement of radioactivity per volume, and liquid chromatography/mass spectrometry analysis for the determination of specific activity. In summary, the NMR-derived values agreed with those from the standard approaches to within 1% to 9% for solution count and specific activity. Additionally, the NMR-derived values for radiochemical purity deviated by less than 5%. A benefit of this method is that these values may be calculated at the same time that (3)H NMR analysis provides the location and distribution of tritium atoms within the molecule. Presented and discussed here is the application of this method, advantages and disadvantages of the approach, and a rationale for utilizing internally calibrated (1)H and (3)H NMR spectroscopy for specific activity, radioactive concentration, and radiochemical purity whenever acquiring (3)H NMR for tritium location.
Asunto(s)
Espectroscopía de Protones por Resonancia Magnética/métodos , Radiofármacos/química , Radiofármacos/normas , Tritio/químicaRESUMEN
A stable adduct of CuI with Bu(4)NI, soluble in organic solvents, has been identified as an effective catalyst for copper-catalyzed C-N and C-O couplings. In addition, stable nonhygroscopic salts of some high performance ligands (diamine MsOH salts/CuX and copper(II) diketonates) were shown to be of similar and sometimes greater reactivity compared to the literature reagents for these couplings. Furthermore, these more robust conditions result in more reproducible results.
Asunto(s)
Cobre/química , Compuestos Organometálicos/química , Compuestos Orgánicos Volátiles/química , Catálisis , Ligandos , Estructura Molecular , Sales (Química)/química , SolubilidadRESUMEN
ADEQUATE experiments provide an alternative to the more commonly employed GHMBC experiment for the establishment of long-range heteronuclear connectivities. The 1,1-ADEQUATE experiment allows the unequivocal identification of both protonated and non-protonated carbon resonances adjacent to a protonated carbon. The 1,n-ADEQUATE experiment establishes correlations via an initial (1)J(CH) heteronuclear transfer followed by an (n)J(CC) out-and-back transfer, most typically, via three carbon-carbon bonds. Hence, the 1,n-ADEQUATE experiment allows the equivalent of (4)J(CH) heteronuclear correlations to be probed when they are not observed in a GHMBC spectrum. Aside from the lower sensitivity of the 1,n-ADEQUATE experiment relative to GHMBC experiments, the interpretation of the former is also complicated by the 'leakage' of (1)J(CC) correlations into the spectrum that must be identified. A method for the inversion of (1)J(CC) correlations to facilitate the interpretation of 1,n-ADEQUATE spectra is presented that allows a single experiment to be performed to access (1)J(CC) and (n)J(CC) correlation information.
Asunto(s)
Espectroscopía de Resonancia Magnética/normas , Carbono/química , Estructura Molecular , Protones , Alcaloides de Pirrolicidina/química , Estándares de ReferenciaRESUMEN
Development of a practical synthesis of MK-7009, a 20-membered [corrected] macrocycle, is described. A variety of ring-closing strategies were evaluated, including ring-closing metathesis, intermolecular palladium-catalyzed cross-couplings, and macrolactamization. Ring closure via macrolactamization was found to give the highest yields under relatively high reaction concentrations. Optimization of the ring formation step and the synthesis of key intermediates en route to MK-7009 are reported.
Asunto(s)
Técnicas de Química Sintética/métodos , Indoles/química , Indoles/síntesis química , Lactamas/química , Compuestos Macrocíclicos/química , Catálisis , Ciclización , Ciclopropanos , Hidrogenación , Isoindoles , Lactamas Macrocíclicas , Leucina/análogos & derivados , Paladio/química , Prolina/análogos & derivados , SulfonamidasRESUMEN
Various dihaloazoles can be monoarylated at a single C-X bond with high selectivity via Suzuki coupling. By changing the palladium catalyst employed, the selectivity can be switched for some dihaloazoles, allowing for Suzuki coupling at the other, traditionally less reactive C-X bond. These conditions are applicable to coupling of a wide variety of aryl-, heteroaryl-, cyclopropyl-, and vinylboronic acids with high selectivities and enable the rapid construction of diverse arrays of diarylazoles in a modular fashion.
Asunto(s)
Hidrocarburos Halogenados/química , Imidazoles/síntesis química , Oxazoles/síntesis química , Tiazoles/síntesis química , Catálisis , Reactivos de Enlaces Cruzados/química , Imidazoles/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Oxazoles/química , Paladio , Estereoisomerismo , Tiazoles/químicaRESUMEN
Treatment of omega-epoxynitriles with hydroxylamine affords cyclic aminonitrones in a single step and with high stereoselectivity. The scope of this novel transformation was explored in a series of examples. The aminonitrone products were shown to be useful substrates for further selective elaboration.
Asunto(s)
Inhibidores de Integrasa VIH/química , Pirimidinonas/química , Cristalografía por Rayos X , Ciclización , Diseño de Fármacos , Inhibidores de Integrasa VIH/síntesis química , Estructura Molecular , Pirimidinonas/síntesis química , Pirrolidinonas/química , Raltegravir PotásicoRESUMEN
A general approach for the synthesis of 3,5-diarylcyclopentenones was developed. Key aspects of this approach are the intramolecular Friedel-Crafts-type cyclization of vinyl chlorides and subsequent Pd-catalyzed cross-coupling reactions. The requisite vinyl chloride-bearing arylacetic acid precursors are readily available by straightforward alkylation of arylacetic acid esters and undergo cyclization to yield 3-chloro-5-aryl-2-cyclopentenones when treated with AlCl(3). The vinylogous acid chloride functionality present in these immediate products allows for further elaboration via Pd-catalyzed cross-coupling chemistry, leading to a diverse array of products.
Asunto(s)
Pentanonas/química , Pentanonas/síntesis química , Cloruro de Vinilo/química , Acilación , Ciclización , Estructura MolecularRESUMEN
Microscale parallel experimentation was used to discover three catalyst systems capable of coupling secondary organotrifluoroborates with sterically and electronically demanding aryl chlorides and bromides. The ensuing results represent the first comprehensive study of alkylboron coupling to aryl chlorides and, in particular, using secondary alkylboron partners. A ligand-dependent beta-hydride elimination/reinsertion mechanism was implicated in the cross-coupling of more hindered substrates, leading to isomeric mixtures of coupled products in some cases.
Asunto(s)
Derivados del Benceno/síntesis química , Boratos/química , Hidrocarburos Bromados/química , Hidrocarburos Clorados/química , Piridinas/síntesis química , Derivados del Benceno/química , Catálisis , Piridinas/químicaRESUMEN
The reactions of chiral benzyl carbocations bearing alpha-phenyl substituents with N-sulfonylated indoles afford 1,1,2-triarylalkanes with anti-selectivities. This outcome is a reversal of facial diastereoselectivity relative to Bach's alpha-alkyl-bearing benzyl cations. The reactions are promoted by either a Brønsted acid (TFA) or Lewis acid (BF3.OEt2), offering differential diastereoselectivities and reactivities. The electronic properties of both reacting partners strongly influence the reaction rates and the product diastereoselectivities and appear to operate under kinetic control. This chemistry provides an efficient access to sterically congested tetrasubstituted ethanes.
Asunto(s)
Alcanos/síntesis química , Indoles/química , Alcanos/química , Alquilación , Derivados del Benceno/química , Catálisis , Técnicas Químicas Combinatorias , Estructura Molecular , EstereoisomerismoRESUMEN
A short and practical synthesis of glucokinase activator 1 was achieved utilizing a convergent strategy involving S(N)Ar coupling of activated aryl fluoride 11 with hydroxypyridine 9. The key to the success of the synthesis was the development of a novel method for enantioselective formation of alpha-arylpyrrolidines during the course of the project. In this method, (-)-sparteine-mediated enantioselective lithiation of N-Boc-pyrrolidine was followed by in situ transmetalation to zinc and Pd-catalyzed coupling with aryl bromide 3, proceeding in 92% ee. This transformation allowed the preparation of compound 1 in a 31% overall yield over six steps.
Asunto(s)
Activadores de Enzimas/síntesis química , Glucoquinasa/metabolismo , Paladio/química , Pirrolidinas/química , Estructura MolecularRESUMEN
This paper describes a remarkably efficient process for the preparation of gamma-secretase inhibitor 1. The target is synthesized in only five steps with an overall yield of 58%. The key operation is a highly selective and practical, crystallization-driven transformation for the conversion of a mixture of tertiary benzylic alcohols into the desired sulfide diastereomer with 94:6 dr. This unprecedented process is based upon a reversible carbon-sulfur bond formation under acidic conditions.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Carbono/química , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Azufre/química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Cristalización , Flúor/química , Cetoácidos/síntesis química , Cetoácidos/química , Magnesio/química , Estructura Molecular , Oxidación-Reducción , Inhibidores de Proteasas/química , Solubilidad , Estereoisomerismo , Sulfuros/química , TemperaturaRESUMEN
The cycloacylation of aniline derivatives to 4-quinolones in the presence of Eaton's reagent is described. This high-yielding methodology is applicable to a wide variety of functionalized anilines and requires milder conditions than those traditionally employed. This cyclization protocol is used to prepare a host of heterocycles and bis-quinolones and is characterized by relatively low reaction temperature and ease of product isolation.
Asunto(s)
Compuestos Heterocíclicos/síntesis química , Quinolonas/síntesis química , Catálisis , Ciclización , Estructura MolecularRESUMEN
We report the first case of a pharmaceutical cocrystal formed between an inorganic acid and an active pharmaceutical ingredient (API), which enabled us to develop a stable crystalline and bioavailable solid dosage form for pharmaceutical development where otherwise only unstable amorphous free form or salts could have been used.
Asunto(s)
Fosfatos/química , Ácidos Fosfóricos/química , Cristalización , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Fosfatos/farmacologíaRESUMEN
A highly efficient synthesis of the potent and selective NK-1 receptor antagonist 1 is described. The key transformation involved the etherification reaction between cyclopentanol 12 and chiral imidate 30 which was catalyzed by HBF4 to initially give ether 14 as a 17:1 mixture of diastereomers and in 75% combined yield. The diastereoselectivity was upgraded to 109:1 by crystallization of the triethylamine solvate 44 which was isolated in 54% yield from 12. Mechanistic studies confirmed that the etherification reaction proceeds through an unprecedented S(N)2 reaction pathway under typical S(N)1 reaction conditions.
Asunto(s)
Ciclopentanos/síntesis química , Antagonistas del Receptor de Neuroquinina-1 , Ciclopentanos/química , Éteres , Estructura MolecularRESUMEN
This communication discloses the first instance of the enantioselective Pd-catalyzed alpha-arylation of N-Boc-pyrrolidine. The methodology relies on Beak's sparteine-mediated, enantioselective deprotonation of N-Boc-pyrrolidine to form the 2-pyrrolidinolithium specices in high enantiomeric ratio (er). Transmetalation of this intermediate with zinc chloride generates the stereochemically rigid, 2-pyrrolidinozinc reagent, which was readily coupled to a variety of functionalized aryl halides at room temperature using a catalyst generated from Pd(OAc)2 and PtBu3-HBF4. A diverse array of 2-aryl-N-Boc-pyrrolidines was synthesized using this methodology, providing adducts consistently in a 96:4 er. A survey of the stoichiometry revealed that as little as 0.3 equiv of zinc could be used in the coupling reaction, and the 2-pyrrolidinozinc reagent was found to exhibit stereochemical stability up to 60 degrees C. The method allows for the most convergent and reliable preparation of a broad range of functionalized 2-aryl-N-Boc-pyrrolidines in high enantioselectivity, which is highlighted in this report by the enantioselective synthesis of (R)-nicotine.
Asunto(s)
Hidrocarburos Aromáticos/química , Pirrolidinas/química , Catálisis , Hidrocarburos Aromáticos/síntesis química , Paladio/química , Pirrolidinas/síntesis química , EstereoisomerismoRESUMEN
[reaction: see text] An efficient five-step synthesis of 1,6-naphthyridone 3b, a p38 mitogen-activated protein (MAP) kinase inhibitor intermediate, in 32% overall yield starting from acetonedicarboxylate (ADC) is described. The synthesis began with a selective monoamidation of ADC dimethyl ester enolate 9. A novel concomitant enamine formation and an imide cyclization afforded the nitrogen differentially protected enamide imide 12. Treatment of 12 with KO(t)Bu and 3-ethoxyacrylate produced lactam 15 quantitatively, which was converted to tetrachloronaphthyridone 19 via a one-pot p-methoxybenzyl (PMB) deprotection and bischlorination. A highly regioselective Pd(OAc)2/IMes-catalyzed Suzuki coupling completed the synthesis.