ABSTRACT
Crown ether fused anilinoquinazoline analogues were synthesized as novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Representative compounds showed potent and selective EGFR inhibitory activities in an in vitro EGFR kinase assay and an EGFR-mediated intracellular tyrosine phosphorylation assay. The synthesis and preliminary biological, physical, and pharmacokinetic evaluation of these fused quinazoline compounds is reported.
Subject(s)
Antineoplastic Agents/pharmacology , Crown Ethers/chemistry , ErbB Receptors/antagonists & inhibitors , Neoplasms, Experimental/drug therapy , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemical synthesis , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , ErbB Receptors/metabolism , Humans , Mice , Models, Molecular , Molecular Structure , Neoplasms, Experimental/pathology , Protein Kinase Inhibitors/administration & dosage , Quinazolines/administration & dosage , Quinazolines/chemical synthesis , Rats , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
A highly efficient Cu-catalyzed C-O bond-forming reaction of alcohol and aryl bromides has been developed. This transformation was realized through the use of copper(I) iodide as a catalyst, 8-hydroxyquinoline as a ligand, and K(3)PO(4) as a base. A variety of functionalized substrates were found to react under these reaction conditions to provide products in good to excellent yields.
Subject(s)
Bromides/chemistry , Carbon/chemistry , Copper/chemistry , Oxygen/chemistry , Catalysis , Ligands , Oxyquinoline/chemistry , Phosphates/chemistry , Potassium Compounds/chemistryABSTRACT
An efficient O-arylation of phenols and aliphatic alcohols with aryl halides was developed that uses an air-stable copper(I) complex as the catalyst. This arylation reaction can be performed in good yield in the absence of Cs2CO3. A variety of functional groups are compatible with these reaction conditions with low catalyst loading levels.
Subject(s)
2,2'-Dipyridyl/chemistry , Copper/chemistry , Ethers/chemical synthesis , Organometallic Compounds/chemistry , Air , Alcohols/chemistry , Catalysis , Hydrocarbons, Halogenated/chemistry , Phenols/chemistryABSTRACT
Synthesis of (+)-disparlure, 1, the sex pheromone of gypsy moth (Lymantria dispar), commenced from cis-vinyl epoxide 4 which was prepared by our asymmetric chloroallylboration in 99% de and 94% ee. Hydroboration of 4 using dicyclohexylborane in THF, followed by sodium perborate oxidation gave a crystalline cis-3,4-epoxy alcohol 3 whose enantiomeric purity was enhanced by recrystallization. Conversion of 3 to (+)-disparlure was via alkylation of the tosylate. (+)-Disparlure was produced in four steps with an overall yield of 27% and >/=99.5% ee.
ABSTRACT
A new method to generate chiral syn-vinylchlorohydrins and cis-vinyloxiranes is reported. Reaction of (alpha-haloallyl)lithiums with methoxy-9-BBN or Ipc(2)BOMe followed by treatment with BF(3).OEt(2) leads to (Z)-(gamma-haloallyl)boranes which react with aldehydes to yield cis-vinylepoxides (de >/= 90%) upon oxidative workup. Alternatively, addition of ethanolamine to the allylboration product yields syn-alpha-halohydrins (de >/= 90%) that are also easily cyclized to cis-vinylepoxides. Extension of this protocol using [(Z)-gamma-chloroallyl]BIpc(2) leads to chiral syn-alpha-chlorohydrins and cis-vinylepoxides in high de (>/=90%) and ee (90-99%). Enantioselectivity of reactions of chiral (Z)-(gamma-chloroallyl)boranes with aldehydes are more sensitive to reaction conditions than enantioselectivity of reactions of other alpha-or gamma-substituted allylboranes. The effects of proportion of BF(3).OEt(2) and the relative efficacies of LiNR(2) bases on diastereo- and enantioselectivity of the chloroallylation are reported.
