ABSTRACT
A scalable synthesis of a potent renin inhibitor (1) is described. The absolute stereochemistry is set via an unprecedented diastereoselective Dieckmann cyclization directed by a remote chiral protecting group. This transformation enables preparation of chiral 1,3-[3.3.1]-diazabicyclononenes by desymmetrization of alkyl-esters, with selectivities ranging from 4 to 17:1.
Subject(s)
Azo Compounds/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Renin/antagonists & inhibitors , Toluene/analogs & derivatives , Azo Compounds/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Crystallography, X-Ray , Cyclization , Molecular Conformation , Molecular Structure , Protease Inhibitors/chemistry , Stereoisomerism , Toluene/chemical synthesis , Toluene/chemistry , Toluene/pharmacologyABSTRACT
We report a practical global deprotection of RNA 2'-O-tert-butyldimethylsilyl (TBS) ethers using commercially available aqueous NH(4)F. The procedure is applicable to both 96-well plate format and large-scale production of RNA. This improved procedure provides a safe, mild, and cost-effective alternative to highly hazardous Et(3)N x 3 HF, a reagent commonly used in the routine synthesis of RNA.
Subject(s)
Oligoribonucleotides/chemistry , Ammonium Compounds , Chromatography, High Pressure Liquid , Fluorides/chemistry , Quaternary Ammonium Compounds/chemistry , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, UltravioletABSTRACT
Practical, chromatography-free syntheses of 5-lipoxygenase inhibitor MK-0633 p-toluenesulfonate (1) are described. The first route used an asymmetric zincate addition to ethyl 2,2,2-trifluoropyruvate followed by 1,3,4-oxadiazole formation and reductive amination as key steps. An improved second route features an inexpensive diastereomeric salt resolution of vinyl hydroxy-acid 22 followed by a robust end-game featuring a through-process hydrazide acylation/1,3,4-oxadiazole ring closure/salt formation sequence to afford MK-0633 p-toluenesulfonate (1).
Subject(s)
Benzenesulfonates/chemical synthesis , Benzopyrans/chemical synthesis , Lipoxygenase Inhibitors , Lipoxygenase Inhibitors/chemical synthesis , Oxadiazoles/chemical synthesis , Arachidonate 5-Lipoxygenase/chemistry , Benzenesulfonates/chemistry , Benzopyrans/chemistry , Lipoxygenase Inhibitors/chemistry , Molecular Structure , Oxadiazoles/chemistry , StereoisomerismABSTRACT
A practical large-scale chromatography-free synthesis of EP4 antagonist MF-310, a potential new treatment for chronic inflammation, is presented. The synthetic route provided MF-310 as its sodium salt in 10 steps and 17% overall yield from commercially available pyridine dicarboxylate 7. The key features of this sequence include a unique regioselective reduction of succinimide 2 controlled by the electronic properties of a remote pyridine ring, preparation of cyclopropane carboxylic acid 3 via a Corey-Chaykovsky cyclopropanation, and a short synthesis of sulfonamide 5.
Subject(s)
Chemistry, Organic/methods , Chemistry, Pharmaceutical/methods , Cyclopropanes/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemical synthesis , Receptors, Prostaglandin E/antagonists & inhibitors , Succinimides/chemistry , Carboxylic Acids/chemistry , Chemistry, Organic/instrumentation , Chemistry, Pharmaceutical/instrumentation , Crystallization , Cyclopropanes/chemistry , Drug Design , Electronics , Heterocyclic Compounds, 3-Ring/chemistry , Models, Chemical , Molecular Structure , Receptors, Prostaglandin E, EP4 Subtype , Stereoisomerism , Sulfonamides/chemistry , Technology, PharmaceuticalABSTRACT
An expedient, five step synthesis of caprolactam 1 is reported starting from natural L-homoserine. The key step is a chemoselective reductive cyclization of alpha,beta-unsaturated nitrile 10 mediated by Raney-Co type metals. This hydrogenation is extensively investigated in order to account for the observed product distribution and yields.
Subject(s)
Cobalt/chemistry , Nitriles/chemistry , Aldehydes/chemical synthesis , Aldehydes/chemistry , Caprolactam/chemistry , Cyclization , Homoserine/chemical synthesis , Homoserine/chemistry , Isomerism , Methionine/chemistry , Molecular Structure , Oxidation-Reduction , TemperatureABSTRACT
Aryl carboxylic esters were synthesized by Pd-catalyzed carbonylation of aryl p-fluorobenzenesulfonates or -tosylates. A unique Josiphos ligand was discovered through high-throughput catalyst screening, which was the key for the successful carbonylation of various substrates. This catalyst is effective and works well for both electron-rich and electron-poor aryl arenesulfonates. Isolated yields of up to 90% were obtained for aryl p-fluorobenzenesulfonates and -tosylates. [reaction: see text]
Subject(s)
Arylsulfonates/chemistry , Hydrocarbons, Fluorinated/chemistry , Tosyl Compounds/chemistry , Catalysis , Combinatorial Chemistry Techniques , Esters , Molecular Structure , PalladiumABSTRACT
The in vitro metabolism of MK-0767 [(+/-)-5-[(2,4-dioxothiazolidin-5-yl) methyl]-2-methoxy-N-[[(4-trifluoromethyl)-phenyl] methyl]benzamide], a novel 2,4-thiazolidinedione (TZD)-containing peroxisome proliferator-activated receptor alpha/gamma agonist, was studied in rat, dog, monkey, and human liver microsomes and hepatocytes, as well as in recombinant human CYP3A4-containing microsomes. Twenty-two metabolites (some at trace levels) were detected by liquid chromatography-tandem mass spectrometry analysis. All appeared to be phase I metabolites except for a glucuronide conjugate of a hydroxylated metabolite that was detected at trace levels. A constant neutral loss scan experiment performed on a triple quadrupole mass spectrometer proved to be very useful for resolving the metabolites from endogenous compounds. It was observed that the initial site of metabolism of MK-0767 was at the TZD ring leading to two major metabolites, namely the 5-hydroxy-TZD metabolite (M24) and the mercapto metabolite (M22). The latter was formed via the cleavage of the TZD ring with the elimination of the carbonyl adjacent to the sulfur atom. The structure of M24 was established by accurate mass measurements and NMR analysis. This hydroxy-TZD metabolite might represent an important precursor for a group of metabolites formed by TZD ring opening and subsequent loss of the sulfur moiety. The mercapto metabolite, on the other hand, is probably the key precursor for the TZD ring-opened metabolites with retention of the sulfur, even though the detailed mechanism of the ring scission remains to be characterized. From these studies, it was concluded that the TZD ring was the major site of metabolism of MK-0767. All the metabolites produced in vitro from human preparations were detected in the corresponding preparations from the nonclinical species.