ABSTRACT
The synthesis of a key intermediate in the preparation of oral antidiabetic drug Saxagliptin is discussed with an emphasis on the challenges posed by the cyclopropanation of a dihydropyrrole. Kinetic studies on the cyclopropanation show an induction period that is consistent with a change in the structure of the carbenoid reagent during the course of the reaction. This mechanistic transition is associated with an underlying Schlenk equilibrium that favors the formation of monoalkylzinc carbenoid IZnCH2I relative to dialkylzinc carbenoid Zn(CH2I)2, which is responsible for the initiation of the cyclopropanation. The factors influencing reaction rates and diastereoselectivities are discussed with the aid of DFT computational studies. The rate accelerations observed in the presence of Brønsted acid-type additives correlate with the minimization of the undesired induction period and offer insights for the development of a robust process.
Subject(s)
Cyclopropanes/chemistry , Pyrroles/chemistry , Zinc/chemistry , Cyclization , Kinetics , Quantum Theory , StereoisomerismABSTRACT
Kinetic studies using reaction calorimetry were conducted under synthetically relevant conditions to study the effect of additives in the cyanation of bromobenzene catalyzed by palladium complexes. This work demonstrates that the addition of a catalytic amount of ZnBr(2) facilitates the reaction with an elimination of the induction period observed without additive. This study afforded a qualitative assessment of the effect of water on the rate-limiting step and the apparent reaction order in bromobenzene.
Subject(s)
Bromobenzenes/chemistry , Nitriles/chemistry , Palladium/chemistry , Bromides/chemistry , Catalysis , Cyanides/chemistry , Kinetics , Organometallic Compounds/chemistry , Water/chemistry , Zinc Compounds/chemistryABSTRACT
A series of P1/P1' substituted cyclic urea analogues were prepared in an attempt to increase the intra-cellular antiviral potency of the nonsymmetrical 3-aminoindazoles DMP 850 and DMP 851. The effect of alkyl substitution of the P1/P1' residues on cellular antiviral potency, protein binding, resistance profile and pharmacokinetics are described.
Subject(s)
HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacology , Urea/analogs & derivatives , Administration, Oral , Animals , Biological Availability , Dogs , Drug Resistance , HIV/drug effects , HIV Protease Inhibitors/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/pharmacology , Hydrophobic and Hydrophilic Interactions , Protein Binding , Structure-Activity RelationshipABSTRACT
DMP 323, a potent HIV-1 protease inhibitor, has been synthesized by an efficient stereoselective process, amenable to large scale preparations. The core C(2) symmetric diol was synthesized by a stereoselective pinacol coupling of CBZ protected D-phenylalanine. Judicious selection of protecting groups allowed cyclic urea formation under mild conditions, enhanced the ease of bis-alkylation, and led to intermediates which were easily purified without chromatography. Additionally, a one-pot, high yield process was developed to prepare the alkylating agent, 4-[(triphenylmethoxy)methyl]benzyl chloride from 1,4-benzenedimethanol.
