Nickel/Bis(oxazoline)-Catalyzed Asymmetric Negishi Arylations of Racemic Secondary Benzylic Electrophiles to Generate Enantioenriched 1,1-Diarylalkanes

A tertiary stereogenic center that bears two different aryl substituents is found in a variety of bioactive compounds, including medicines such as Zoloft and Detrol. We have developed an efficient method for the synthesis of enantioenriched 1,1-diarylalkanes from readily available racemic benzylic alcohols. Formation of a benzylic mesylate (which is not isolated), followed by treatment with an arylzinc reagent, LiI, and a chiral nickel/bis­(oxazoline) catalyst, furnishes the Negishi cross-coupling product in high ee and good yield. A wide array of functional groups (e.g., an aryl iodide, a thiophene, and an <i>N</i>-Boc-indole) are compatible with the mild reaction conditions. This method has been applied to a gram-scale synthesis of a precursor to Zoloft

Nickel/Bis(oxazoline)-Catalyzed Asymmetric Negishi Arylations of Racemic Secondary Benzylic Electrophiles to Generate Enantioenriched 1,1-Diarylalkanes

A tertiary stereogenic center that bears two different aryl substituents is found in a variety of bioactive compounds, including medicines such as Zoloft and Detrol. We have developed an efficient method for the synthesis of enantioenriched 1,1-diarylalkanes from readily available racemic benzylic alcohols. Formation of a benzylic mesylate (which is not isolated), followed by treatment with an arylzinc reagent, LiI, and a chiral nickel/bis­(oxazoline) catalyst, furnishes the Negishi cross-coupling product in high ee and good yield. A wide array of functional groups (e.g., an aryl iodide, a thiophene, and an <i>N</i>-Boc-indole) are compatible with the mild reaction conditions. This method has been applied to a gram-scale synthesis of a precursor to Zoloft

Identification and Characterization of Potential Impurities of Dronedarone Hydrochloride

Six potential process related impurities were detected during the impurity profile study of an antiarrhythmic drug substance, Dronedarone (<b>1</b>). Simple high performance liquid chromatography and liquid chromatography–mass spectrometry methods were used for the detection of these process impurities. Based on the synthesis and spectral data (MS, IR, ¹H NMR, ¹³C NMR, and DEPT), the structures of these impurities were characterized as 5-amino-3-[4-(3-di-<i>n</i>-butylaminopropoxy)­benzoyl]-2-<i>n</i>-butylbenzofuran (impurity I); <i>N</i>-(2-butyl-3-(4-(3-(dibutylamino)­propoxy)­benzoyl)­benzofuran-5-yl)-<i>N</i>-(methylsulfonyl)­methanesulfonamide (impurity II); <i>N</i>-(2-butyl-3-(4-(3-(dibutylamino)­propoxy)­benzoyl)­benzofuran-5-yl)-1-chloromethanesulfonamide (impurity III); <i>N</i>-{2-propyl-3-[4-(3-dibutylaminopropoxy)­benzoyl]­benzofuran-5-yl}­methanesulfonamide (impurity IV); <i>N</i>-(2-butyl-3-(4-(3-(dibutylamino)­propoxy)­benzoyl)­benzofuran-5-yl)­formamide (impurity V); and (2-butyl-5-((3-(dibutylamino)­propyl)­amino)­benzofuran-3-yl)­(4-(3-(dibutylamino)­propoxy)­phenyl)­methanone (impurity VI). The synthesis and characterization of these impurities are discussed in detail

Practical, Asymmetric Route to Sitagliptin and Derivatives: Development and Origin of Diastereoselectivity

The development of a practical and scalable process for the asymmetric synthesis of sitagliptin is reported. Density functional theory calculations reveal that two noncovalent interactions are responsible for the high diastereoselection. The first is an intramolecular hydrogen bond between the enamide NH and the boryl mesylate SO, consistent with MsOH being crucial for high selectivity. The second is a novel C–H···F interaction between the aryl C5-fluoride and the methyl of the mesylate ligand