Improved Process for the Preparation of 1-Benzhydrylazetidin-3-ol: Development of an Efficient Synthesis and Identification of Process-related Impurities and/or Intermediates

Abstract

An improved, one-pot, and multikilogram-scale synthesis of 1-benzhydrylazetidin-3-ol, the pharmaceutically important moiety, has been developed. The improved process for the preparation of 1-benzhydrylazetidin-3-ol was able to minimize a content of impurities and allows the effective production of 1-benzhydrylazetidin-3-ol and its scale-up. The process was high yielding (80%) and chromatography-free with purity 99.3 area %.

Highly Regioselective and Efficient Synthesis of Aminoepoxides by Ring Closure of Aminohalohydrins Mediated by KF-Celite

“…This transformation has been described using simple organic (tert-butoxides 22,23 ) or inorganic bases (hydroxides 24,25 ); although yields are generally high, the major drawback for the ring closure is the regioselective control. Furthermore, as noted very recently by Madhsudhan and co-workers, 26,27 for 1-amino-3-chloropropan-2-ols (which constitutively present two potential nucleophilic sites, the amino group and the hydroxyl one), the unique ring closure reaction product observed in the presence of sodium bicarbonate is the azetidine, 28 without any detection of the epoxide (Scheme 1).…”

3-((Hetera)cyclobutyl)azetidines, “Stretched” Analogues of Piperidine, Piperazine, and Morpholine: Advanced Building Blocks for Drug Discovery

“…The organic layer was separated, washed with 10% aq NaHCO 3 (3 × 50 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure to give the title compound. White solid, mp 114–116 °C (lit . mp 115–116 °C); 98% yield (19.5 g).…”

“…1-Benzhydrylazetidin-3-yl methanesulfonate (9). 48,49 Et 3 N (13.1 mL, 94.0 mmol) was added to a solution of 1-benzhydrylazetidin-3-ol (8) (15.0 g, 62.7 mmol) in CH 2 Cl 2 (150 mL), and reaction mixture was cooled to −20 °C. Methanesulfonyl chloride (8.61 g, 75.2 mmol) was added dropwise maintaining the temperature below −20 °C.…”

Synthesis of Novel Hybrid 4H-Pyran-lipoic and 4H-Pyran-azetidine Derivatives

“…28 Formation of alcohol 9 was carried out through reaction between diphenylmethanamine and epichlorohydrin as the first step, the mixture was stirred with isopropanol at room temperature to generate the epoxide opening product; upon completion of this reaction (TLC), the solvent was evaporated and an acetonitrile/methanol mixture was added in combination with triethylamine as base, then heated to reflux until 9 was obtained in equal yields as reported. 29…”