RESUMO
An expedient synthesis of N-unsubstituted 1,2,3-triazole-4-carboxylates has been demonstrated through [3 + 2] cycloaddition of sodium azide with α-haloacrylates. The process is highly reliable and exhibits an unusually wide scope with respect to α-fluoro-, α-chloro-, α-bromo-, and α-iodoacrylates. The potential of selected 1,2,3-triazole-4-carboxylates in the preparation of 1,5-dihydro-4H-[1,2,3]-triazolo-[4,5-c]-quinolin-4-one has also been illustrated.
Assuntos
Acrilatos/química , Hidrocarbonetos Halogenados/química , Azida Sódica/química , Triazóis/síntese química , Ciclização , Estrutura Molecular , Triazóis/químicaRESUMO
An exceptionally stereoselective and general synthesis of (Z)-α-haloacrylates, ready to undergo various synthetic transformations, has been demonstrated from α-haloacetates and aldehydes in a one-pot manner via the titanium-enolate based asymmetric aldol condensation. Besides being an expedient synthetic procedure, the ready availability of diverse α-haloacetates, exceptional stereoselectivity, and high yields make the process a versatile transformation in organic synthesis. The potential of this method in up-scaling operations has been illustrated.
Assuntos
Acetatos/química , Acrilatos/síntese química , Aldeídos/química , Alcenos/síntese química , Hidrocarbonetos Halogenados/química , Titânio/química , Acrilatos/química , Alcenos/química , Estrutura Molecular , EstereoisomerismoRESUMO
We report herein an efficient route for the synthesis of 2,4,8-trichloropyrido[3,2-d]pyrimidines 1 with R(1) substituents at C-6. The potential of such scaffolds was demonstrated by the possibility to displace regioselectively each aromatic chloride to introduce diversity. Sequential sulfur nucleophilic addition followed by Liebeskind-Srogl cross-coupling reaction yielded unprecedented aryl introduction at C-4 on a trichloropyrido[3,2-d]pyrimidine derivative. The reactivity difference of the remaining two chlorides toward S(N)Ar reactions was investigated. Amination yielded high C-2 regioselectivity, while thiolation was influenced by C-6 substituents, resulting in medium to high C-2 versus C-8 regioselectivity. The last chloride was efficiently displaced by S(N)Ar, Suzuki-Miyaura cross-coupling reaction, or reduction. C-2 arylation as a final step was also possible by Liebeskind-Srogl cross-coupling reaction on the previously introduced C-2 thioether. A concise and highly divergent synthetic use of 1 was developed, thereby providing an efficient approach to explore the structure-activity relationship of pyrido[3,2-d]pyrimidine derivatives such as 9, 10, 15, and 16.
Assuntos
Reagentes de Ligações Cruzadas/química , Piridinas/química , Pirimidinas/química , Pirimidinas/síntese química , Catálise , Modelos Moleculares , Estrutura Molecular , EstereoisomerismoRESUMO
We report herein the synthesis of 4-amino-2,8-dichloropyrido[3,2-d]pyrimidine derivatives 2 and their regioselective diversification through S(N)Ar and metal-catalyzed cross-coupling reactions. While amination of 2 took place selectively at C-2, the regioselectivity of thiol or thiolate addition depended on the reaction conditions. Selective C-8 addition was obtained in DMF with Hünig's base and C-2 addition in (i)PrOH. These C-2 or C-8 regioselective thiolations provided an opportunistic way to selectively activate either of the two positions toward the metal-catalyzed cross-coupling reaction. The chloride could be efficiently substituted by Suzuki-Miyaura reaction and the sulfanyl group by Liebeskind-Srogl cross-coupling reaction, demonstrating the orthogonality of both reactive centers. The development of regioselective conditions for these different transformations yielded the synthesis of 4-amino-2,6,8-trisubstituted pyrido[3,2-d]pyrimidine derivatives, with various substituents.
Assuntos
Pirimidinas/síntese química , Aminação , Catálise , Reagentes de Ligações Cruzadas , Ésteres , Estrutura Molecular , Pirimidinas/química , EstereoisomerismoRESUMO
New phenoxyacetic acid antagonists of CRTH2 are described. Following the discovery of a hit compound by a focused screening, high protein binding was identified as its main weakness. Optimization aimed at reducing serum protein binding led to the identification of several compounds that showed not only excellent affinities for the receptor (41 compounds with K(i) < 10 nM) but also excellent potencies in a human whole blood assay (IC(50) < 100 nM; PGD2-induced eosinophil shape change). Additional optimization of the PK characteristics led to the identification of several compounds suitable for in vivo testing. Of these, 19k and 19s were tested in two different pharmacological models (acute FITC-mediated contact hypersensitivity and ovalbumin-induced eosinophilia models) and found to be active after oral dosing (10 and 30 mg/kg).
Assuntos
Acetatos/síntese química , Alcinos/síntese química , Antialérgicos/síntese química , Anti-Inflamatórios/síntese química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Sulfonas/síntese química , Acetatos/farmacocinética , Acetatos/farmacologia , Administração Oral , Alcinos/farmacocinética , Alcinos/farmacologia , Animais , Antialérgicos/farmacocinética , Antialérgicos/farmacologia , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Ligação Competitiva , Proteínas Sanguíneas/metabolismo , Células CACO-2 , Permeabilidade da Membrana Celular , Forma Celular , Quimiotaxia de Leucócito , Dermatite de Contato/tratamento farmacológico , Eosinófilos/efeitos dos fármacos , Eosinófilos/patologia , Eosinófilos/fisiologia , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Ovalbumina/imunologia , Fenoxiacetatos , Ligação Proteica , Eosinofilia Pulmonar/tratamento farmacológico , Eosinofilia Pulmonar/imunologia , Ensaio Radioligante , Ratos , Relação Estrutura-Atividade , Sulfonas/farmacocinética , Sulfonas/farmacologiaRESUMO
PTSA-ZnCl2 has been proved to be an efficient and mild catalyst for the synthesis of 3,5-disubstituted-1,2,4-oxadiazoles from amidoximes and organic nitriles.
Assuntos
Benzenossulfonatos/química , Cloretos/química , Nitrilas/química , Oxidiazóis/síntese química , Oximas/química , Compostos de Zinco/química , Catálise , Oxidiazóis/químicaRESUMO
Benzalaminoacetals (1), upon refluxing with trifluoroacetic acid, lead to 2-benzylpyrazines, rather than the expected isoquinolines. This unusual reaction represents another useful way to prepare a variety of 2-benzylpyrazines from the corresponding benzaldehydes.
Assuntos
Acetais/química , Benzeno/química , Pirazinas/síntese química , Ácido Trifluoracético/química , Estrutura Molecular , Pirazinas/químicaRESUMO
A facile synthesis of alpha,beta-unsaturated carboxylic acids from gem-dibromomethylarenes is described. gem-Dibromomethylarenes are employed for the first time in the Knoevenagel-Doebner reaction as aldehyde equivalents for the efficient synthesis of alpha,beta-unsaturated carboxylic acids.