ABSTRACT
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.
Subject(s)
Acrylates/chemistry , Hydrocarbons, Halogenated/chemistry , Sodium Azide/chemistry , Triazoles/chemical synthesis , Cyclization , Molecular Structure , Triazoles/chemistryABSTRACT
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.
Subject(s)
Acetates/chemistry , Acrylates/chemical synthesis , Aldehydes/chemistry , Alkenes/chemical synthesis , Hydrocarbons, Halogenated/chemistry , Titanium/chemistry , Acrylates/chemistry , Alkenes/chemistry , Molecular Structure , StereoisomerismABSTRACT
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.
Subject(s)
Cross-Linking Reagents/chemistry , Pyridines/chemistry , Pyrimidines/chemistry , Pyrimidines/chemical synthesis , Catalysis , Models, Molecular , Molecular Structure , StereoisomerismABSTRACT
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.
Subject(s)
Pyrimidines/chemical synthesis , Amination , Catalysis , Cross-Linking Reagents , Esters , Molecular Structure , Pyrimidines/chemistry , StereoisomerismABSTRACT
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).
Subject(s)
Acetates/chemical synthesis , Alkynes/chemical synthesis , Anti-Allergic Agents/chemical synthesis , Anti-Inflammatory Agents/chemical synthesis , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Sulfones/chemical synthesis , Acetates/pharmacokinetics , Acetates/pharmacology , Administration, Oral , Alkynes/pharmacokinetics , Alkynes/pharmacology , Animals , Anti-Allergic Agents/pharmacokinetics , Anti-Allergic Agents/pharmacology , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Binding, Competitive , Blood Proteins/metabolism , Caco-2 Cells , Cell Membrane Permeability , Cell Shape , Chemotaxis, Leukocyte , Dermatitis, Contact/drug therapy , Eosinophils/drug effects , Eosinophils/pathology , Eosinophils/physiology , Female , HEK293 Cells , Humans , Mice , Mice, Inbred BALB C , Microsomes, Liver/metabolism , Ovalbumin/immunology , Phenoxyacetates , Protein Binding , Pulmonary Eosinophilia/drug therapy , Pulmonary Eosinophilia/immunology , Radioligand Assay , Rats , Structure-Activity Relationship , Sulfones/pharmacokinetics , Sulfones/pharmacologyABSTRACT
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.
Subject(s)
Benzenesulfonates/chemistry , Chlorides/chemistry , Nitriles/chemistry , Oxadiazoles/chemical synthesis , Oximes/chemistry , Zinc Compounds/chemistry , Catalysis , Oxadiazoles/chemistryABSTRACT
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.
Subject(s)
Acetals/chemistry , Benzene/chemistry , Pyrazines/chemical synthesis , Trifluoroacetic Acid/chemistry , Molecular Structure , Pyrazines/chemistryABSTRACT
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.