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1.
J Org Chem ; 84(8): 4661-4669, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30388009

RESUMO

The development of an improved short and efficient commercial synthesis of the JAK2 inhibitor, a complex pyrrolopyridine, BMS-911543, is described. During the discovery and development of this synthesis, a Pd-catalyzed C-H functionalization was invented which enabled the rapid union of the key pyrrole and imidazole fragments. The synthesis of this complex, nitrogen-rich heterocycle was accomplished in only six steps (longest linear sequence) from readily available materials.


Assuntos
Compostos Heterocíclicos com 3 Anéis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Catálise , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Ligantes , Estrutura Molecular , Paládio/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química
2.
J Org Chem ; 83(18): 11133-11144, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-30102035

RESUMO

Two efficient asymmetric routes to γ-secretase modulator BMS-932481, under investigation for Alzheimer's disease, have been developed. The key step for the first route involves a challenging enantioselective hydrogenation of an unfunctionalized trisubstituted alkene to establish the benzylic stereocenter, representing a very rare case of achieving high selectivity on a complex substrate. The second route demonstrates the first example of a vinylogous dynamic kinetic resolution (VDKR) ketone reduction, where the carbonyl and the racemizable stereocenter are not contiguous, but are conjugated through a pyrimidine ring. Not only did this transformation require both catalyst and substrate control to correctly establish the two stereocenters, but it also necessitated that the nonadjacent benzylic center of the ketone substrate be more acidic than that of the alcohol product to make the process dynamic. DFT computations aided the design of this novel VDKR pathway by reliably predicting the relative acidities of the intermediates involved.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Compostos de Anilina/química , Compostos de Anilina/síntese química , Pirimidinas/química , Pirimidinas/síntese química , Compostos de Anilina/farmacologia , Catálise , Técnicas de Química Sintética , Ciclização , Teoria da Densidade Funcional , Hidrogenação , Cetonas/química , Cinética , Oxirredução , Pirimidinas/farmacologia , Estereoisomerismo
3.
J Am Chem Soc ; 137(41): 13272-81, 2015 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-26461028

RESUMO

Kinetic, spectroscopic, crystallographic, and computational studies probing a Pd-catalyzed C-H arylation reaction reveal that mono-oxidation of the bis-phosphine ligand is critical for the formation of the active catalyst. The bis-phosphine mono-oxide is shown to be a hemilabile, bidentate ligand for palladium. Isolation of the oxidative addition adduct, with structural elucidation by X-ray analysis, showed that the mono-oxide was catalytically competent, giving the same reaction rate in the productive reaction as the Pd(II)/xantphos precursor. A dual role for the carboxylate base in both catalyst activation and reaction turnover was demonstrated, along with the inhibiting effect of excess phosphine ligand. The generality of the role of phosphine mono-oxide complexes in Pd-catalyzed coupling processes is discussed.


Assuntos
Paládio/química , Fosfinas/química , Xantenos/química , Catálise , Cristalografia por Raios X , Cinética , Espectroscopia de Ressonância Magnética , Oxirredução
5.
J Am Chem Soc ; 131(25): 8798-804, 2009 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-19507853

RESUMO

A highly efficient synthesis of sitagliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM), has been developed. The key dehydrositagliptin intermediate 9 is prepared in three steps in one pot and directly isolated in 82% yield and >99.6 wt % purity. Highly enantioselective hydrogenation of dehydrositagliptin 9, with as low as 0.15 mol % of Rh(I)/(t)Bu JOSIPHOS, affords sitagliptin, which is finally isolated as its phosphate salt with nearly perfect optical and chemical purity. This environmentally friendly, 'green' synthesis significantly reduces the total waste generated per kilogram of sitagliptin produced in comparison with the first-generation route and completely eliminates aqueous waste streams. The efficiency of this cost-effective process, which has been implemented on manufacturing scale, results in up to 65% overall isolated yield.


Assuntos
Inibidores da Dipeptidil Peptidase IV/síntese química , Química Verde/métodos , Pirazinas/síntese química , Triazóis/síntese química , Química Verde/economia , Hidrogenação , Fosfato de Sitagliptina , Estereoisomerismo
7.
J Chromatogr A ; 1145(1-2): 149-54, 2007 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-17300788

RESUMO

The suitability of the Eksigent Express 800 microfluidic eight-channel HPLC instrument for multiparallel normal-phase chiral analysis in support of high-throughput pharmaceutical process research was investigated. Analysis of test mixtures containing the two enantiomers of benzoin and the closely related (R,S)-dihydrobenzoin, was carried out in a 96-well microplate, affording rapid (<2 h) and accurate assessment of enantiopurity. In a second example, use of the instrument to support high-throughput catalyst screening of the asymmetric hydrogenation of a prochiral unsaturated ester is presented, in which method development (gradient screening of four columns and two eluents, followed by optimization to afford a fast analytical method) and analysis of a 96-well microplate was carried out within a single working day. This represents a considerable improvement over conventional analysis techniques that usually take several days to complete.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Microfluídica/métodos , Benzoína/química , Hidrogenação , Microfluídica/instrumentação , Estrutura Molecular , Reprodutibilidade dos Testes , Estereoisomerismo
8.
ACS Chem Neurosci ; 7(12): 1635-1640, 2016 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-27744678

RESUMO

Combination studies of neurokinin 1 (NK1) receptor antagonists and serotonin-selective reuptake inhibitors (SSRIs) have shown promise in preclinical models of depression. Such a combination may offer important advantages over the current standard of care. Herein we describe the discovery and optimization of an indazole-based chemotype to provide a series of potent dual NK1 receptor antagonists/serotonin transporter (SERT) inhibitors to overcome issues of ion channel blockade. This effort culminated in the identification of compound 9, an analogue that demonstrated favorable oral bioavailability, excellent brain uptake, and robust in vivo efficacy in a validated depression model. Over the course of this work, a novel heterocycle-directed asymmetric hydrogenation was developed to facilitate installation of the key stereogenic center.


Assuntos
Antidepressivos/farmacologia , Indazóis/farmacologia , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Administração Oral , Animais , Antidepressivos/síntese química , Antidepressivos/química , Antidepressivos/toxicidade , Transtorno Depressivo/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Gerbillinae , Humanos , Indazóis/síntese química , Indazóis/química , Indazóis/toxicidade , Camundongos , Estrutura Molecular , Antagonistas dos Receptores de Neurocinina-1/síntese química , Antagonistas dos Receptores de Neurocinina-1/química , Antagonistas dos Receptores de Neurocinina-1/toxicidade , Ratos , Receptores da Neurocinina-1/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/toxicidade , Relação Estrutura-Atividade , Regulador Transcricional ERG/metabolismo
9.
Org Lett ; 7(22): 4935-8, 2005 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-16235926

RESUMO

[reaction: see text] The catalytic asymmetric hydrogenation of enamine amides and esters with catalyst Rh-1a, prepared from ferrocenyl based ligand 1a or 1b and [(COD)RhCl](2), has been shown through kinetic studies to suffer from product inhibition. Enamine ester substrates have also been shown to be incompatible with the amine products of the reaction in methanol. In situ protection of the amine products with di-tert-butyl dicarbonate eliminates functional group incompatibility of ester substrates and eliminates product inhibition in the reaction.


Assuntos
Aminas/química , Catálise , Hidrogenação , Metanol/química , Estrutura Molecular , Ródio/química
10.
Org Lett ; 14(18): 4938-41, 2012 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-22954228

RESUMO

An enantioselective synthesis of the CGRP antagonist BMS-846372, amenable to large scale preparation, is presented. This new synthesis showcases a chemo- and enantioselective reduction of a cyclohepta[b]pyridine-5,9-dione as well as a Pd-catalyzed alpha-arylation reaction to form the key carbon-carbon bond and set the absolute and relative stereochemistry.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Catálise , Compostos Heterocíclicos de 4 ou mais Anéis/química , Estrutura Molecular , Estereoisomerismo
11.
Org Lett ; 12(5): 1032-5, 2010 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-20146430

RESUMO

The development of a general and mild method for Pd-catalyzed alpha-arylation of a variety of ketones bearing multiple heteroatoms is described. The ligand to metal ratio and the position of the heteroatoms with respect to the carbonyl moiety significantly impact the efficiency of these transformations. In addition, these conditions were successfully applied to the alpha-arylation of cyclic imines. A detailed investigation of the scope of this methodology, including the effect of the ligand to metal ratio, is discussed.


Assuntos
Cetonas/química , Catálise , Concentração de Íons de Hidrogênio , Ligantes , Paládio/química
12.
J Am Chem Soc ; 128(51): 17063-73, 2006 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-17177459

RESUMO

Ruthenium complexes employing axially chiral ligands were found to be effective asymmetric hydrogenation catalysts for the reduction of alpha,beta-unsaturated ene acid 1-E to give 2, a prostaglandin D2 (PGD2) receptor antagonist. With [(S-BINAP)Ru(p-cymene)Cl2]2 (3, S-BINAP = (S)-(+)-2,2'-bis(diphenylphospino)-1,1'-binapthyl), it was discovered that low hydrogen pressures (<30 psi) were essential to achieve high enantioselectivities (92% ee). A detailed mechanistic study was undertaken to elucidate this pressure dependence. It was determined that compound 1-E is in a ruthenium-catalyzed equilibrium with endocylic isomer 1-Endo and in photochemical equilibrium with Z isomer 1-Z. Each isomer could be hydrogenated to give 2, albeit with different rates and enantioselectivities. Hydrogenation of 1-Endo with 3 was found to give 2 in high enantiomeric excess, regardless of pressure and at a rate substantially faster than that of hydrogenation of 1-E and 1-Z. In contrast, isomers 1-E and 1-Z exhibited pressure-dependent enantioselectivities, with higher enantiomeric excesses obtained at lower pressures. A rationale for this pressure dependence is described. Deuterium labeling studies with 1-Endo and tiglic acid were used to elucidate the mechanism of hydride insertion and product release from ruthenium. Under neutral conditions, protonolysis was the major pathway for metal-carbon cleavage, while under basic conditions, hydrogenolysis of the metal-carbon bond was predominant.


Assuntos
Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Alcenos/química , Ácidos Carboxílicos/química , Deutério/química , Hidrogênio/química , Hidrogenação , Cinética , Estrutura Molecular , Pressão , Estereoisomerismo , Temperatura
13.
J Am Chem Soc ; 126(32): 9918-9, 2004 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-15303855

RESUMO

A direct asymmetric hydrogenation of unprotected enamino esters and amides is described. Catalyzed by Rh complexes with Josiphos-type chiral ligands, this method gives beta-amino esters and amides in high yield and high ee (93-97% ee). No acyl protection/deprotection is required.


Assuntos
Amidas/síntese química , Aminas/química , Aminoácidos/química , Ésteres/síntese química , Alcenos/química , Catálise , Hidrogenação , Estereoisomerismo
14.
Proc Natl Acad Sci U S A ; 101(16): 5776-81, 2004 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-15079059

RESUMO

An efficient asymmetric synthesis of a selective estrogen receptor modulator (SERM) that has a dihydrobenzoxathiin core structure bearing two stereogenic centers is reported. The stereogenic centers were established by an unprecedented chiral sulfoxide-directed stereospecific reduction of an alpha,beta-unsaturated sulfoxide to the saturated sulfide in one step. Studies to elucidate the mechanism for this reduction are reported. Highly efficient Cu(I)-mediated ether formation was used to install the ether side chain, and selective debenzylation conditions were developed to remove the benzyl protecting groups on the phenols.


Assuntos
Boranos/química , Moduladores de Receptor Estrogênico/síntese química , Safrol/análogos & derivados , Safrol/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Oxirredução , Estereoisomerismo
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