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1.
J Org Chem ; 85(13): 8339-8351, 2020 07 02.
Artículo en Inglés | MEDLINE | ID: mdl-32462862

RESUMEN

An efficient general methodology for the synthesis of 4-quinolinyl ethers is demonstrated via a highly reactive SNAr reaction of 4-quinolinyl sulfones with a range of structurally diversified 1°, 2°, and 3° alcohols with a wide substrate scope and high yields. By adapting this methodology, a convergent synthesis of a complex target of HCV NS3/4a protease inhibitor BI 201420 was accomplished.


Asunto(s)
Hepatitis C , Proteínas no Estructurales Virales , Antivirales , Éteres , Hepacivirus , Humanos , Inhibidores de Proteasas/farmacología , Sulfonas
2.
J Org Chem ; 84(8): 4926-4931, 2019 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-30715884

RESUMEN

The application of a Buchwald's third generation palladacycle containing a dihydrobenzooxaphosphole-based ligand (e.g., BIDIME) was reported in the Suzuki cross-coupling reaction. Using flow technology, high yield and reproducible Suzuki cross-coupling reaction for one of our key intermediates was achieved with Pd loadings as low as 0.5 mol %. This continuous flow approach overcomes catalyst deactivation and scale dependence issues that can be a problem in some traditional batch-mode operations and responds to the challenge of improving process greenness.

3.
J Labelled Comp Radiopharm ; 62(2): 77-85, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30466143

RESUMEN

The drug candidates (2) and (3) are highly potent LFA-1 inhibitors. They were efficiently prepared labeled with carbon-14 using a palladium-catalyzed carboxylation of an iodo-precursor (5) and sodium formate-14 C to afford acid [14 C]-(6), which was coupled via an amide bond to chiral amines (7) and (8) in 52% and 48% overall yield, respectively, and with specific activities higher than 56 mCi/mmol and radiochemical purities of 99%. For stable isotopes synthesis, the amine [2 H8 ]-(7) was synthesized in three steps from 2-cyanopyridine-2 H4 using Kulinkovich-Szymonik aminocyclopropanation, followed by coupling to L-alanine-2,3,3,3-2 H4 -N-t-BOC, and then removal of the BOC-protecting group. Amide bond formation with acid (6) gave [2 H8 ]-(2) in 36% overall yield. The amine [13 C4 ,15 N]-(8) was obtained in two steps using L-threonine-14 C4 ,15 N and then coupled to acid [13 C]-(6) to give [13 C5 ,15 N]-(3) in 56% overall yield.


Asunto(s)
Radioisótopos de Carbono/química , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Radiofármacos/síntesis química , Unión Proteica , Radiofármacos/farmacología
4.
J Org Chem ; 83(3): 1448-1461, 2018 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-29323903

RESUMEN

A chromatography-free, asymmetric synthesis of the C2-symmetric P-chiral diphosphine t-Bu-SMS-Phos was developed using a chiral auxiliary-based approach in five steps from the chiral auxiliary in 36% overall yield. Separtion and recovery of the auxiliary were achieved with good yield (97%) to enable recycling of the chiral auxiliary. An air-stable crystalline form of the final ligand was identified to enable isolation of the final ligand by crystallization to avoid chromatography. This synthetic route was applied to prepare up to 4 kg of the final ligand. The utility of this material was demonstrated in the asymmetric hydrogenation of trifluoromethyl vinyl acetate at 0.1 mol % Rh loading to access a surrogate for the pharmaceutically relavent chiral trifluoroisopropanol fragment in excellent yield and enantiomeric excess (98.6%).

5.
J Org Chem ; 82(10): 5456-5460, 2017 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-28459568

RESUMEN

An efficient and practical synthesis of enantiomerically pure P-chiral dihydrobenzooxaphosphole (BOP) core 1 is developed that is amenable to large scale preparation of the related ligand series. The unique epimerization of the P-chiral center of the undesired (R,R)-diastereomeric phosphine oxide 19 through chlorination followed by crystallization makes this chemical resolution method achieve 65% yield of desired (R,S)-diastereomer 12.

6.
J Am Chem Soc ; 138(47): 15473-15481, 2016 11 30.
Artículo en Inglés | MEDLINE | ID: mdl-27794616

RESUMEN

A concise asymmetric synthesis of an 11ß-HSD-1 inhibitor has been achieved using inexpensive starting materials with excellent step-economy at low catalyst loadings. The catalytic enantioselective total synthesis of 1 was accomplished in 7 steps and 38% overall yield aided by the development of an innovative, sequential strategy involving Pd-catalyzed pyridinium C-H arylation and Ir-catalyzed asymmetric hydrogenation of the resulting fused tricyclic indenopyridinium salt highlighted by the use of a unique P,N-ligand (MeO-BoQPhos) with 1000 ppm of [Ir(COD)Cl]2.


Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Piperidinas/síntesis química , Piperidinas/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Catálisis , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Hidrogenación , Iridio/química , Conformación Molecular , Paladio/química , Piperidinas/química , Estereoisomerismo
7.
J Org Chem ; 81(6): 2665-9, 2016 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-26909738

RESUMEN

An efficient asymmetric synthesis of 11-ß-HSD inhibitor 1 has been accomplished in five linear steps and 53% overall yield, starting from the readily available 3-chloro-1-phenylpropan-1-one. The key feature of the synthesis includes an asymmetric methallylation of 3-chloro-1-phenylpropan-1-one catalyzed by the highly effective organocatalyst (S)-3,3'-F2-BINOL under solvent-free and metal-free conditions.


Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Naftoles/síntesis química , Propano/análogos & derivados , 11-beta-Hidroxiesteroide Deshidrogenasas/química , Catálisis , Cetonas/química , Naftoles/química , Propano/síntesis química , Propano/química , Estereoisomerismo
8.
Angew Chem Int Ed Engl ; 54(24): 7144-8, 2015 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-25939331

RESUMEN

A practical and efficient synthesis of a complex chiral atropisomeric HIV integrase inhibitor has been accomplished. The combination of a copper-catalyzed acylation along with the implementation of the BI-DIME ligands for a ligand-controlled Suzuki cross-coupling and an unprecedented bis(trifluoromethane)sulfonamide-catalyzed tert-butylation renders the synthesis of this complex molecule robust, safe, and economical. Furthermore, the overall synthesis was conducted in an asymmetric and diastereoselective fashion with respect to the imbedded atropisomer.


Asunto(s)
Inhibidores de Integrasa VIH/síntesis química , Integrasa de VIH/química , VIH/enzimología , Acilación , Catálisis , Cobre/química , Integrasa de VIH/metabolismo , Inhibidores de Integrasa VIH/química , Humanos , Ligandos , Estereoisomerismo , Sulfonamidas/química
9.
J Org Chem ; 78(8): 3616-35, 2013 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-23544738

RESUMEN

The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H3PO4 (1·H3PO4) is presented. A key trifluoromethyl ketone intermediate 22 containing an N-(4-methoxyphenyl)ethyl amide was prepared by an enolization/bromine-magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone 22 gave the desired diastereomer in 32% yield and with dr = 98:2 from a 1:1 diastereomeric mixture after crystallization. Subsequently, an asymmetric propargylation was developed which provided the desired diastereomer in 4:1 diastereoselectivity and 75% yield with dr = 99:1 after crystallization. The azaindole moiety was efficiently installed by a one-pot cross coupling/indolization reaction. An efficient deprotection of the 4-methoxyphenethyl group was developed using H3PO4/anisole to produce the anisole solvate of the API in high yield and purity. The final form, a phosphoric acid cocrystal, was produced in high yield and purity and with consistent control of particle size.


Asunto(s)
Amidas/química , Benzamidas/química , Glucocorticoides/agonistas , Glucocorticoides/química , Piridinas/química , Pirroles/química , Estructura Molecular , Estereoisomerismo
10.
Org Lett ; 15(7): 1710-3, 2013 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-23527954

RESUMEN

(S)-3,3'-F2-BINOL has been synthesized for the first time and demonstrated as a highly active organocatalyst for asymmetric methallylation of ketones. Up to 98:2 enantioselectivity and 99% yield were obtained with 5 mol % catalyst loading. The catalyst (S)-3,3'-F2-BINOL could be easily recovered and reused.


Asunto(s)
Cetonas/química , Naftoles/química , Catálisis , Estructura Molecular , Estereoisomerismo
11.
Curr Radiopharm ; 5(4): 314-7, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22724423

RESUMEN

Morpholine-4-carboxylic acid {(S)-1-[4-cyano-1-(3-morpholin-4-yl-propyl)-piperidin-4-ylcarbamoyl]-4,4- dimethyl-hexyl}-amide, (1) is a potent reversible and selective cathepsin S inhibitor. Deuterium labeled (1) was prepared in four steps in 62% overall yield from [2H8]- morpholine and chiral acid (6). Carbon-14 labeled (1) was obtained in two steps using sodium [14C]-cyanide in a modified Strecker reaction followed by amide bond formation with acid (6) in 74% overall radiochemical yield. The phosphate salt of this compound was produced by treatment with phosphoric acid in methanol in 97% yield.


Asunto(s)
Radioisótopos de Carbono/química , Catepsinas/antagonistas & inhibidores , Deuterio/síntesis química , Morfolinas/síntesis química , Piperidinas/síntesis química
12.
Drug Metab Dispos ; 40(6): 1122-9, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22393120

RESUMEN

11-Ethyl-5,11-dihydro-5-methyl-8-[2-[(1-oxido-4-quinolinyl)oxy] ethyl]-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (BILR 355) is an inhibitor of the human immunodeficiency virus-1. BILR 355 exhibited a nonlinear pharmacokinetic profile and low exposure after oral administration to humans. This article describes the in vitro metabolism of BILR 355, which is correlated with the in vivo nonlinearity findings. Our in vitro studies had demonstrated that BILR 355 was extensively metabolized by cytochrome P450 3A. Thus, BILR 355 was concomitantly administered with ritonavir (RTV) in an attempt to boost systemic exposure, which did occur in humans. In addition, the expectation was that the overall metabolism of BILR 355 would be decreased with concomitant administration of RTV. Subsequent metabolite profiling was performed using human plasma samples obtained from clinical phase Ib studies with concomitant administration of BILR 355 and RTV. A total of 18 metabolites was observed. Their structures were proposed on the basis of high-performance liquid chromatography-tandem mass spectrometry technologies, and 10 metabolites were confirmed by comparison with synthetic standards. We were surprised to find that a disproportionate human metabolite, BILR 516, was uncovered during this metabolite profiling study and pharmacokinetic analysis of BILR 516 showed that it had a longer half-life and higher exposure than the parent compound at steady state. Of interest, BILR 516 was not detected in human plasma when BILR 355 was administered alone. Therefore, whereas RTV boosted the exposure of BILR 355, it resulted in a significant metabolic switching of BILR 355. Overall, this article demonstrates an unusual example of metabolic switching and raises concern about the consequence of metabolic switching during drug development.


Asunto(s)
Azepinas/metabolismo , Azepinas/farmacología , Citocromo P-450 CYP3A/metabolismo , Piridinas/metabolismo , Piridinas/farmacología , ADN Polimerasa Dirigida por ARN/metabolismo , Ritonavir/metabolismo , Ritonavir/farmacología , Azepinas/química , Estudios de Cohortes , Interacciones Farmacológicas/fisiología , Humanos , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Piridinas/química , Ritonavir/química
13.
J Org Chem ; 75(4): 1155-61, 2010 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-20102230

RESUMEN

A potent reversible inhibitor of the cysteine protease cathepsin-S was prepared on large scale using a convergent synthetic route, free of chromatography and cryogenics. Late-stage peptide coupling of a chiral urea acid fragment with a functionalized aminonitrile was employed to prepare the target, using 2-hydroxypyridine as a robust, nonexplosive replacement for HOBT. The two key intermediates were prepared using a modified Strecker reaction for the aminonitrile and a phosphonation-olefination-rhodium-catalyzed asymmetric hydrogenation sequence for the urea. A palladium-catalyzed vinyl transfer coupled with a Claisen reaction was used to produce the aldehyde required for the side chain. Key scale up issues, safety calorimetry, and optimization of all steps for multikilogram production are discussed.


Asunto(s)
Alquenos/síntesis química , Catepsinas/antagonistas & inhibidores , Catepsinas/química , Inhibidores Enzimáticos/síntesis química , Urea/síntesis química , Compuestos de Vinilo/síntesis química , Alquenos/química , Calorimetría/métodos , Catálisis , Ciclización , Inhibidores Enzimáticos/farmacología , Indicadores y Reactivos/química , Modelos Moleculares , Estructura Molecular , Paladio/química , Rodio/química , Estereoisomerismo , Urea/química , Compuestos de Vinilo/química
14.
J Org Chem ; 73(4): 1524-31, 2008 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-18197688

RESUMEN

The reduction of tertiary phosphine oxides (TPOs) and sulfides with diisobutylaluminum hydride (DIBAL-H) has been studied in detail. An extensive solvent screen has revealed that hindered aliphatic ethers, such as MTBE, are optimum for this reaction at ambient temperature. Many TPOs undergo considerable reduction at ambient temperature and then stall due to inhibition. 31P and 13C NMR studies using isotopically labeled substrates as well as competition studies have revealed that the source of this inhibition is tetraisobutyldialuminoxane (TIBAO), which builds up as the reaction proceeds. TIBAO selectively coordinates the TPO starting material, preventing further reduction. Several strategies have been found to circumvent this inhibition and obtain full conversion with this extremely inexpensive reducing agent for the first time. Practical reduction protocols for these critical targets have been developed.


Asunto(s)
Compuestos Organometálicos/química , Óxidos/química , Fosfinas/química , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Oxidación-Reducción
15.
Org Lett ; 10(2): 341-4, 2008 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-18095698

RESUMEN

Asymmetric hydrogenation of unsaturated urea esters with the BIPI Ligands has been examined. Optimization of the P-N ligand structure has led to the development of chiral rhodium catalysts capable of producing the targets with >99% ee. The critical phosphine borane SNAr reaction needed for ligand synthesis has been optimized to give the adducts in high yield at ambient temperature with no racemization. An extremely concise, economical, and scalable sequence to these important new ligands for catalysis of asymmetric hydrogenation has been developed.


Asunto(s)
Fosfinas/química , Rodio/química , Urea/análogos & derivados , Urea/química , Catálisis , Ésteres , Hidrogenación , Ligandos , Estructura Molecular , Estereoisomerismo
16.
J Org Chem ; 72(11): 4250-3, 2007 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-17447813

RESUMEN

A sequential allyl vinyl ether formation-Claisen rearrangement process catalyzed by a palladium(II)-phenanthroline complex is reported. The effects of allylic alcohol structure, type of vinylating agent, and palladium catalysts are discussed. This method provides a convenient approach to gamma,delta-unsaturated aldehydes under mild conditions that avoid the use of toxic Hg(II) catalysts. The new methodology has been successfully demonstrated on the kilogram scale.


Asunto(s)
Aldehídos/síntesis química , Paladio/química , Fenantrolinas/química , Propanoles/química , Compuestos de Vinilo/química , Aldehídos/química , Catálisis , Estereoisomerismo , Termodinámica
17.
Org Lett ; 7(19): 4277-80, 2005 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-16146406

RESUMEN

[reaction: see text] Diisobutylaluminum hydride (DIBAL-H) and triisobutylaluminum have been found to be outstanding reductants for secondary phosphine oxides (SPOs). All classes of SPOs can be readily reduced, including diaryl, arylalkyl, and dialkyl members. Many SPOs can now be reduced at cryogenic temperatures, and conditions for preservation of reducible functional groups have been found. Even the most electron-rich and sterically hindered phosphine oxides can be reduced in a few hours at 50-70 degrees C. This new reduction has distinct advantages over existing technologies.


Asunto(s)
Óxidos/química , Fosfinas/química , Aluminio/química , Ligandos , Estructura Molecular , Oxidación-Reducción
18.
Magn Reson Chem ; 43(12): 1032-9, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16142832

RESUMEN

Four unknown trace impurities (7-10) were observed in the capsule formulation of the HIV drug Tipranavir after prolonged storage at 30 degrees C/70% RH. Extensive NMR and LC/MS analyses revealed the compounds to be covalent adducts between TRIS, an excipient of the formulation, and diastereomeric Tipranavir alcohols formed via slow air oxidation of the drug substance. The structures were ultimately confirmed by total synthesis with final purification by chiral, preparative supercritical fluid chromatography. A novel Favorskii rearrangement to furnish butyrolactones was also uncovered during the synthesis.


Asunto(s)
Contaminación de Medicamentos , Piridinas/química , Piridinas/síntesis química , Pironas/química , Pironas/síntesis química , Alcoholes/química , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura Molecular , Sulfonamidas
19.
J Org Chem ; 70(8): 2904-11, 2005 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-15822948

RESUMEN

This paper describes an efficient kinetic resolution process of trisubstituted cyclic olefins via a chiral dioxirane generated in situ from a fructose-derived ketone and Oxone. The substrates presented include a variety of 1,3-disubstituted and 1,6-disubstituted cyclohexenes with the stereogenic centers at allylic positions. A sequential desymmetrization and kinetic resolution of 1,4-cyclohexadienes by the chiral dioxirane was also found to be feasible. The initially formed monoepoxides can be kinetically resolved by continuing the reaction, leading to the increase or decrease of the ee values of monoepoxides depending on the diene systems. In some cases, a prochiral directing group is not required and the first formed epoxide stereoselectively directs the second epoxidation. When the coupled desymmetrization and kinetic resolution is used synergistically, high enantiopurity can be obtained for an epoxide from an intrinsically less enantioselective substrate. The observed absolute and relative stereochemistry as well as the changing optical purity can be effectively rationalized by transition state analysis.


Asunto(s)
Alquenos/química , Compuestos Epoxi/química , Cetonas/química , Cinética , Estructura Molecular , Estereoisomerismo
20.
J Org Chem ; 69(16): 5187-95, 2004 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-15287760

RESUMEN

The Boehringer-Ingelheim phosphinoimidazoline (BIPI) ligands were applied to the formation of chiral quaternary centers in the asymmetric Heck reaction. Several different substrates were examined in detail, using more than 70 members of this new ligand class. Hammett relationships were determined through systematic variation of the ligand electronics. All substrates showed essentially the same Hammett behavior, where enantioselectivity increased as the ligands were made more electron-deficient. Ligand optimization has led to catalysts which give the highest enantioselectivities reported to date for these difficult systems.

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