Lisa F. Frey

Practical synthesis of a highly functionalized thiazole ketone

Abstract Compound 1 is a uniquely substituted ketone prepared via addition of a thiazole anion to an aromatic nitrile in good overall yield. An exploration into the generality of the addition of thiazole anions to nitriles allowed us to make a variety of thiazole ketones in good to excellent yields. The non-odorous thiolate-mediated demethylation reaction used in the synthesis of 1 is also presented.

Practical routes toward the synthesis of 2-halo- and 2-alkylamino-4-pyridinecarboxaldehydes

Abstract We recently required an efficient synthesis of 2-halo- and 2-alkylamino-4-pyridinecarboxaldehydes. Several routes to these compounds were investigated resulting in efficient and practical procedures from readily available and inexpensive starting materials.

Evaluation of non-conventional polar modifiers on immobilized chiral stationary phases for improved resolution of enantiomers by supercritical fluid chromatography

An evaluation of the use of non-conventional polar modifiers for the supercritical fluid chromatographic separation of enantiomers on immobilized chiral stationary phases is presented. The resolution of a group of nine commercially available racemates is studied on the Chiralpak IA, IB, IC, ID, IE, and IF chiral stationary phases using CO2-based eluents containing non-conventional polar modifiers such as dichloromethane, chloroform, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, acetone, ethyl acetate, toluene, 2,2,2-trifluoroethanol, and N,N-dimethylformamide. Screening experiments and method development for the commercial racemates on the immobilized columns with the non-conventional solvents demonstrated an ability to adjust the retention and improve resolution. From these results we were able to assign a general eluotropic relationship between the non-conventional solvents and methanol. A general ability to selectively adjust chromatographic retention while improving analyte solubility can lead to improved preparative chromatographic performance.

A practical preparation of 5-(ketoaryl)thiazoles

Abstract This article describes a facile synthesis of 2-substituted-5-(ketoaryl)thiazoles, which are important intermediates for the synthesis of biologically active compounds. A variety of 2-substituted thiazole anions were added to aryl nitriles to provide the desired ketones after aqueous hydrolysis.

Practical enantioselective synthesis of a COX-2 specific inhibitor

Abstract Two synthetic strategies to the COX-2 specific inhibitor 1 have been described that allowed its preparation in large quantities in 79% overall yield from (S)-2-hydroxy-2-methylbutyric acid. These studies have led to the identification of an efficient resolution of (±)-2-hydroxy-2-methylbutyric acid and a novel thionyl chloride aided formation of amide 11 from acid 6 .

A Practical Synthesis of 2-Butyl-4(5)-chloro-5(4)-hydroxymethyl- 1H-imidazole

Abstract A practical process for the synthesis of 2-butyl-4-hydroxymethyl imidazole (4) followed by chlorination to provide chloroimidazole 1 in an overall 71% yield has been developed.

Identification and structural elucidation of process impurities generated in the end-game synthesis of taranabant (MK-0364) via cyanuric chloride

Taranabant (MK-0364) is a highly potent and selective cannabinoid-1 receptor (CB-1R) inverse agonist. It is being developed at Merck & Company to treat obesity. The chemical synthesis of MK-0364 drug substance involved the direct coupling of chiral amine and pyridine acid side chains mediated by cyanuric chloride. Four major process impurities were observed and characterized using high performance liquid chromatography (HPLC) coupled with ultraviolet (UV) and electrospray ionization (ESI) mass spectrometry (MS) detectors. The exact mass data was used for structural elucidation which suggests that the impurities are derivatives of cyanuric chloride formed in the coupling step. Owing to the reactive nature of these impurities, an interesting degradation phenomenon was observed during stability testing of MK-0364 drug substance when stored at 40 degrees C/75% RH and 25 degrees C/60% RH conditions. Degradation pathways were proposed to explain the changes observed in the HPLC impurity profile. Forced degradation experiments were also conducted to confirm the degradation pathways and assess the stability of the impurities. Finally, the complete stability data of the bulk drug are reported to support the hypothesis.