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 N-Boc-indole) are compatible with the mild reaction conditions. This method has been applied to a gram-scale synthesis of a precursor to Zoloft™.
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.
Six
potential process related impurities were detected during the
impurity profile study of an antiarrhythmic drug substance, Dronedarone
(1). 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-n-butylaminopropoxy)benzoyl]-2-n-butylbenzofuran (impurity I); N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)-N-(methylsulfonyl)methanesulfonamide (impurity II); N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)-1-chloromethanesulfonamide
(impurity III); N-{2-propyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl}methanesulfonamide
(impurity IV); N-(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.
Milnacipran is a cyclopropane derivative, used as an anti depressant drug. During the process development of milnacipran, four process related potential impurities were detected in high performance liquid chromatography. All these impurities were identified, synthesized and subsequently characterized by their respective spectral data (IR, LC-MS, 1 H NMR, and 13 C NMR) as described in this article.
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