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1.
J Org Chem ; 84(8): 4780-4795, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30475616

RESUMO

An asymmetric synthesis of HCV NS5B nucleoside polymerase inhibitor (1) is described. This novel route features several remarkably diastereoselective and high-yielding transformations, including construction of the all-carbon quaternary stereogenic center at C-2 via a thermodynamic aldol reaction. A subsequent glycosylation reaction with activated uracil via C-1 phosphate and installation of the cyclic phosphate group using an achiral phosphorus(III) reagent followed by oxidation provides 1.


Assuntos
Antivirais/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Humanos , Estrutura Molecular , Estereoisomerismo , Proteínas não Estruturais Virais/metabolismo
2.
Analyst ; 144(9): 2872-2880, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30830135

RESUMO

Modern process research and development can often be hampered by the tedious method development required to chromatographically resolve mixtures of chemical species with very similar physical properties. Herein, we describe a simple approach for the development and implementation of an efficient ultra-high performance liquid chromatography (UHPLC) assay that is extensively applied to the separation and analysis of multicomponent reaction mixtures of closely related pharmaceutical intermediates and impurities. Methods are optimized using multi-column and multi-solvent UHPLC screening in conjunction with chromatography simulation software (ACD Labs/LC Simulator). This approach is implemented to enable the separation, identification, mapping and control of impurities formed within the process chemistry optimization of the dimeric catalyst used in the synthesis of new drug substances. The final method utilized a sub-2 µm C18 stationary phase (2.1 mm I.D. × 50 mm length, 1.7 µm particle size ACQUITY UPLC BEH C18) with a non-conventional chaotropic mobile phase buffer (35 mM potassium hexafluorophosphate in 0.1% phosphoric acid/acetonitrile) in order to achieve baseline separation of all reaction components. The chromatographic simulation and modeling strategy served to generate 3D resolution maps with robust separation conditions that match the outcome of subsequent experimental data (overall ΔtR < 0.35%). Our multi-column UHPLC screening with computer-assisted chromatographic modeling is a great addition to the toolbox of synthetic chemists and can be a powerful tool for streamlining process chemistry optimization in organic chemistry laboratories across both academic and industrial sectors.


Assuntos
Carbamatos/isolamento & purificação , Cromatografia Líquida de Alta Pressão/métodos , Compostos Heterocíclicos com 2 Anéis/isolamento & purificação , Cromatografia Líquida de Alta Pressão/instrumentação , Simulação por Computador
3.
J Org Chem ; 81(2): 723-8, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26656787

RESUMO

Low temperature NMR studies revealed that a diastereoselective Mannich reaction between a phenyl oxazolidone-derived titanium enolate and an aromatic aldimine was found to occur only after introduction of a proton source. While various protic additives could be used to promote the transformation, the best results were obtained using AcOH to afford the corresponding Mannich products in high diastereoselectivities and yields.

4.
Org Lett ; 24(27): 4860-4864, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35793545

RESUMO

A general and diastereoselective fluorination/glycosylation strategy for the synthesis of 2'-fluorinated nucleosides has been developed. Electrophilic fluorination of a glycal with NFSI provided the 1',2'-difunctionalized furanoside intermediate with high diastereoselectivity. The TBS-protected 2'-deoxyfluorosulfonimide sugar was prepared on an 80 g scale and isolated as a crystalline, bench-stable single diastereomer. This intermediate was found to undergo a subsequent glycosylation reaction with a variety of heteroaryl nucleophiles with generally good diastereoselectivities.


Assuntos
Halogenação , Nucleosídeos , Glicosilação , Estereoisomerismo
5.
Chem Sci ; 12(26): 9031-9036, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34276931

RESUMO

An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl3/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides.

6.
Artigo em Inglês | MEDLINE | ID: mdl-29477066

RESUMO

Impurity fate and purge studies are critical in order to establish an effective impurity control strategy for approval of the commercial filing application of new medicines. Reversed phase liquid chromatography-diode array-mass spectrometry (RPLC-DAD-MS) has traditionally been the preferred tool for impurity fate mapping. However, separation of some reaction mixtures by LC can be very problematic requiring combination LC-UV for area % analysis and a different LC-MS method for peak identification. In addition, some synthetic intermediates might be chemically susceptible to the aqueous conditions used in RPLC separations. In this study, the use of supercritical fluid chromatography-photodiode array-electrospray ionization mass spectrometry (SFC-PDA-ESIMS) for fate and purge of two specified impurities in the 1-uridine starting material from the synthesis of a bis-piv 2'keto-uridine, an intermediate in the synthesis of uprifosbuvir, a treatment under investigation for chronic hepatitis C infection. Readily available SFC instrumentation with a Chiralpak IC column (4.6 × 150 mm, 3 µm) and ethanol: carbon dioxide based mobile phase eluent enabled the separation of closely related components from complex reaction mixtures where RLPC failed to deliver optimal chromatographic performance. These results illustrate how SFC combined with PDA and ESI-MS detection can become a powerful tool for direct impurity fate mapping across multiple reaction steps.


Assuntos
Química Farmacêutica/métodos , Cromatografia com Fluido Supercrítico/métodos , Contaminação de Medicamentos/prevenção & controle , Preparações Farmacêuticas , Espectrometria de Massas por Ionização por Electrospray/métodos , Modelos Moleculares , Preparações Farmacêuticas/análise , Preparações Farmacêuticas/química , Preparações Farmacêuticas/normas
7.
Science ; 356(6336): 426-430, 2017 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-28450641

RESUMO

The catalytic stereoselective synthesis of compounds with chiral phosphorus centers remains an unsolved problem. State-of-the-art methods rely on resolution or stoichiometric chiral auxiliaries. Phosphoramidate prodrugs are a critical component of pronucleotide (ProTide) therapies used in the treatment of viral disease and cancer. Here we describe the development of a catalytic stereoselective method for the installation of phosphorus-stereogenic phosphoramidates to nucleosides through a dynamic stereoselective process. Detailed mechanistic studies and computational modeling led to the rational design of a multifunctional catalyst that enables stereoselectivity as high as 99:1.


Assuntos
Amidas/síntese química , Antineoplásicos/síntese química , Antivirais/síntese química , Nucleosídeos/síntese química , Ácidos Fosfóricos/síntese química , Pró-Fármacos/síntese química , Catálise , Simulação por Computador , Estereoisomerismo
8.
Org Lett ; 18(22): 5888-5891, 2016 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-27802043

RESUMO

A scalable and efficient synthesis of the GPR40 agonist MK-8666 was developed from a simple pyridine building block. The key step to set the stereochemistry at two centers relied on an enzymatic dynamic kinetic reduction of an unactivated ketone. Directed evolution was leveraged to generate an optimized ketoreductase that provided the desired trans alcohol in >30:1 dr and >99% ee. Further, it was demonstrated that all four diastereomers of this hydroxy-ester could be prepared in high yield and selectivity. Subsequently, a challenging intramolecular displacement was carried out to form the cyclopropane ring system with perfect control of endo/exo selectivity. The endgame coupling strategy relied on a Pd-catalyzed C-O coupling to join the headpiece chloropyridine with the benzylic alcohol tailpiece.

9.
Org Lett ; 5(13): 2271-4, 2003 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-12816426

RESUMO

Nucleophilic displacement of readily available alpha,alpha-dibromoketones with excess morpholine gave the corresponding ketoaminals, which upon condensation with aminoguanidine in MeOH in the presence of AcOH afforded 5-substituted-3-amino-1,2,4-triazines in >95% regioselectivity and 45-76% isolated yield. [reaction: see text]

11.
Org Lett ; 16(10): 2716-9, 2014 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-24786635

RESUMO

A novel synthesis of vernakalant is described. Using inexpensive and readily available reagents, the key transformations involve (1) an efficient zinc-amine-promoted etherification, (2) a highly stereoselective enzyme-catalyzed dynamic asymmetric transamination to set up the two contiguous chiral centers in the cyclohexane ring, and (3) a pyrrolidine ring formation via alkyl-B(OH)2-catalyzed amidation and subsequent imide reduction.


Assuntos
Anisóis/síntese química , Pirrolidinas/síntese química , Aminação , Aminas/química , Anisóis/química , Catálise , Cloretos/química , Cicloexanos , Estrutura Molecular , Pirrolidinas/química , Estereoisomerismo , Compostos de Zinco/química
12.
Org Lett ; 12(3): 512-5, 2010 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-20028132

RESUMO

Dynamic kinetic resolution (deracemization) of various alpha-alkyl-substituted beta-ketoamides 1 via asymmetric transfer hydrogenation proceeded efficiently to give the corresponding syn-beta-hydroxy amides 3 in high diastereo- and enantioselectivities. Specifically, subjection of 1 to HCO(2)H and Et(3)N in the presence of 0.5-1 mol % of pentafluorobenzenesulfonyl-DPEN-Ru catalyst 2b at 30-40 degrees C in either PhCH(3) or CH(2)Cl(2) generated the syn-hydroxy product 3 selectively in 15-33:1 dr, 93-97% ee, and 75-88% isolated yields.


Assuntos
Amidas/síntese química , beta-Lactamas/síntese química , Amidas/química , Catálise , Técnicas de Química Combinatória , Hidrogenação , Cinética , Estrutura Molecular , Estereoisomerismo , beta-Lactamas/química
13.
J Org Chem ; 73(4): 1639-42, 2008 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-18186647

RESUMO

Asymmetric hydrogenation of allylic dimethylcarbinamide 2 with 1 mol % of cationic Rh(I)-Josiphos complex in THF under 500 psi of H2 generated the corresponding tertiary carbinamide 1 in 98.5% assay yield and a 94:6 enantiomeric ratio. Upon crystallization, the product was isolated in 91% isolated yield and 95:5 enantiomeric ratio.


Assuntos
Amidas/química , Hidrogênio/química , Rênio/química , Catálise , Cristalização , Espectroscopia de Ressonância Magnética , Espectrofotometria Infravermelho
14.
J Org Chem ; 70(6): 2372-5, 2005 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-15760235

RESUMO

[reaction: see text] An asymmetric synthesis of (S)-gamma-fluoroleucine ethyl ester 1 is described. The key transformation involves a lipase-catalyzed dynamic ring-opening of 2-(3-butenyl)azlactone 7b with EtOH to give amide ester (S)-6b in 84% enantiomeric excess. Removal of the N-pentenoyl group with N,N'-dibromodimethylhydantoin in the presence of trifluoroacetic acid afforded the titled compound, which was isolated as its hydrogen sulfate salt in 75% yield and >97% ee.


Assuntos
Glicoesfingolipídeos/síntese química , Lipase/química , Catálise , Conformação Molecular , Estereoisomerismo
15.
J Org Chem ; 70(15): 5938-45, 2005 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-16018689

RESUMO

A convergent, practical, and efficient synthesis of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (1), an orally active GABA(A) alpha(2/3)-selective agonist, is described. The seven-step, chromatography-free synthesis was demonstrated on a multi-kilogram scale and utilized biaryl bromide 6 and imidazotriazine 22 as key intermediates. Biaryl bromide 6 was prepared via a highly selective aromatic bromination. The regioselective condensation of aminotriazine 15 with chloroacetaldehyde provided the desired imidazotriazine intermediate 22. A highly regioselective palladium-catalyzed arylation in the final step highlights the efficiency of the route.


Assuntos
Agonistas GABAérgicos/síntese química , Hidrocarbonetos Aromáticos/química , Imidazóis/química , Paládio/química , Triazinas/síntese química , Acetaldeído/análogos & derivados , Acetaldeído/química , Brometos/química , Catálise , Receptores de GABA-A , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/química
16.
J Am Chem Soc ; 125(52): 16310-21, 2003 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-14692772

RESUMO

Highly functionalized, cyclobutene-containing adducts are afforded through intramolecular cycloadditions between cyclobutadiene and tethered dienes. The cycloaddition displays the following reactivity trend: cyclobutadiene serves as a dienophile in intramolecular reactions when it is connected to the diene through a four-atom tether. In cases where a three-atom linker separates the two reaction partners, the cyclobutadiene can function as both a diene and dienophile, affording a mixture of vinylcyclobutane (2 + 2) and cyclohexene-containing cycloadducts (4 + 2). Theoretical studies provide insight into the factors influencing the various pericyclic pathways operative in this system. In cases where cyclobutadiene functions as a diene to generate vinylcyclobutanes, these (2 + 2) adducts can be converted into the corresponding (4 + 2) cyclohexenyl products through a [3,3]-sigmatropic rearrangement.


Assuntos
Ciclobutanos/química , Cicloparafinas/química , Compostos Bicíclicos com Pontes/síntese química , Éteres/química , Modelos Moleculares , Termodinâmica
17.
J Am Chem Soc ; 124(49): 14748-58, 2002 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-12465988

RESUMO

Intramolecular cycloadditions between cyclobutadiene and olefins can provide highly functionalized cyclobutene-containing products. The outcome of the reaction depends on the nature of the tether connecting the two reactive partners in the cycloaddition. Electronically unactivated olefins attached to cyclobutadiene through a three-atom, heteroatom-containing tether yield successfully the desired cycloadducts, whereas the corresponding substrates without a heteroatom linkage or with a longer tether are less prone to undergo the intramolecular cycloaddition. Calculations were used to help uncover some of the factors that influence the course of the cycloaddition. Successful intramolecular reactions usually require either electronic activation of the dienophile, conformational restriction of the tether, or a slower oxidation protocol. In general, a facile intermolecular dimerization of cyclobutadiene is the major process that competes with the intramolecular cycloaddition.


Assuntos
Alcenos/química , Hidrocarbonetos Aromáticos com Pontes/síntese química , Ciclobutanos/química , Modelos Moleculares , Oxirredução , Termodinâmica
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