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1.
J Org Chem ; 84(8): 4873-4892, 2019 04 19.
Article in English | MEDLINE | ID: mdl-30629443

ABSTRACT

Dasabuvir (1) is an HCV polymerase inhibitor which has been developed as a part of a three-component direct-acting antiviral combination therapy. During the course of the development of the synthetic route, two novel coupling reactions were developed. First, the copper-catalyzed coupling of uracil with aryl iodides, employing picolinamide 16 as the ligand, was discovered. Later, the palladium-catalyzed sulfonamidation of aryl nonaflate 33 was developed, promoted by electron-rich palladium complexes, including the novel phosphine ligand, VincePhos (50). This made possible a convergent, highly efficient synthesis of dasabuvir that significantly reduced the mutagenic impurity burden of the process.


Subject(s)
Antiviral Agents/pharmacology , Enzyme Inhibitors/pharmacology , Hepacivirus/drug effects , Palladium/chemistry , Sulfonamides/pharmacology , Uracil/analogs & derivatives , Viral Nonstructural Proteins/antagonists & inhibitors , 2-Naphthylamine , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Catalysis , Drug Development , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hepacivirus/enzymology , Microbial Sensitivity Tests , Molecular Structure , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Uracil/chemical synthesis , Uracil/chemistry , Uracil/pharmacology , Viral Nonstructural Proteins/metabolism
2.
Org Lett ; 11(4): 947-50, 2009 Feb 19.
Article in English | MEDLINE | ID: mdl-19178160

ABSTRACT

A general and practical method for the preparation of unsymmetrically substituted ureas has been developed utilizing palladium-catalyzed amidation. Both aryl bromides and chlorides, as well as heteroaryl chlorides, have been coupled to aryl, benzyl, and aliphatic ureas by using a novel nonproprietary bipyrazole ligand (bippyphos).


Subject(s)
Palladium/chemistry , Urea/analogs & derivatives , Urea/chemical synthesis , Catalysis , Combinatorial Chemistry Techniques , Molecular Structure , Urea/chemistry
3.
J Org Chem ; 69(11): 3907-11, 2004 May 28.
Article in English | MEDLINE | ID: mdl-15153024

ABSTRACT

Olefin cross metathesis (CM) was applied to the synthesis of 6-O-substituted erythromycin derivatives. The reactions were catalyzed by transition metal alkylidene complexes, particularly bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (Grubbs' first-generation catalyst). This approach allowed for the elaboration of the 6-O-allyl group of highly functionalized macrolides at various stages of the synthetic sequence, affording 6-O-3-aryl-propenyl products with excellent E-selectivity. Little or no self-dimerization of the reacting components was found in the crude mixtures. Preliminary kinetic data accounts for the observed cross-selectivity based on substrate reactivity and steric factors.


Subject(s)
Alkenes/chemistry , Erythromycin/chemical synthesis , Catalysis , Erythromycin/analogs & derivatives , Molecular Structure , Organometallic Compounds/chemistry , Ruthenium , Stereoisomerism
4.
J Org Chem ; 68(23): 8847-52, 2003 Nov 14.
Article in English | MEDLINE | ID: mdl-14604353

ABSTRACT

Functionalized erythromycin 9-oxime derivatives are 6-O-allylated under mild conditions using substituted allyl tert-butyl carbonates under palladium(0) catalysis. This allylation works well where traditional ether-forming protocols function poorly. Allyl tert-butyl carbonates provide higher yields in this reaction than lesser substituted carbonates such as ethyl or isopropyl. Aryl-substituted allyl carbonates or carbamates may be employed as well and, when used, produce trans-olefinic products.


Subject(s)
Alcohols/chemistry , Erythromycin/chemistry , Alkylation
5.
J Org Chem ; 68(21): 8092-6, 2003 Oct 17.
Article in English | MEDLINE | ID: mdl-14535788

ABSTRACT

A palladium catalysis-mediated approach to coupling aliphatic alcohols with allyl carbonates has been developed. The method allows for the allylation of primary, secondary, and tertiary alcohols efficiently under mild conditions. Limitations were explored as well as the asymmetric application of the chemistry. Regiochemical and olefin geometry was controlled in the coupling of unsymmetrical allylating agents. Transient allyl carbonates were observed in the coupling, which comprised the trans-carboxylation of the allyl-carbonate with the requisite alcohol.

6.
J Org Chem ; 63(17): 5903-5907, 1998 Aug 21.
Article in English | MEDLINE | ID: mdl-11672194

ABSTRACT

An impurity observed during the synthesis of zileuton (Zyflo) has been isolated and characterized as a benzo[b]thiophene derivative that has undergone electrophilic substitution in the 6 position (4). A nine-step synthesis confirms the structural assignment. Key steps in the synthesis include a regioselective Friedel-Crafts coupling between 2-hydroxythioanisole, 8, and 1-(benzo[b]thien-2-yl)ethanol, 1, and formation of a benzo[b]thiophene from an o-methylthiobenzaldehyde, 14, and chloroacetone. The synthesis provides a potentially general route to substituted benzo[b]thiophenes.

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