Cyclodextrins (CD) are a family of cyclic oligosaccharides composed of α-(1,4) linked glucopyranose subunits. According to the general accepted nomenclature of cyclodextrins an α (alpha)-cyclodextrin is a 6-membered ring molecule, a β (beta)-cyclodextrin is a 7-membered ring molecule and a γ (gamma)-cyclodextrin is a 8-membered ring molecule. Cyclodextrins are useful molecular chelating agents. They possess a cage-like supramolecular structure. As a result of molecular complexation phenomena CDs are widely used in many industrial products, technologies and analytical methods.
The γ (gamma)-cyclodextrin with a commercial interest is sugammadex. A key intermediate for preparing Sugammadex is 6-per-deoxy-6-per-chloro-γ-cyclodextrin of formula I.

The preparation of 6-per-deoxy-6-per-chloro-γ-cyclodextrin is disclosed in WO2012/025937. This document discloses the preparation of 6-per-deoxy-6-per-chloro-γ-cyclodextrin by chlorination of γ-cyclodextrin with a halogenating agent prepared from phosphorous pentachloride and dimethylformamide. After completion of the chlorination the solvent is removed to obtain a viscous residue. The viscous residue is diluted with water followed by adjusting the pH 8 with 5M sodium hydroxide to obtain a slurry. Said slurry is then filtered, washed with water and dried to give 6-per-deoxy-6-per-chloro-γ-cyclodextrin. The process disclosed in WO2012/025937A1 suffers from the following disadvantages:                (i) The halogenating agent, which is prepared by reaction of phosphorous pentachloride and dimethylformamide, produces numerous phosphorous species on reaction with dimethylformamide, and its subsequent use for the halogenation of γ-cyclodextrin also produces phosphate esters as impurities which are difficult to remove.        (ii) The removal of dimethylformamide after chlorination of γ-cyclodextrin gives highly viscous oil, which is very cumbersome to stir.        (iii) The filtration of 6-per-deoxy-6-per-chloro-γ-cyclodextrin is also very challenging due to its amorphous nature and it takes very long time for the filtration.        (iv) The purity of 6-per-deoxy-6-per-chloro-γ-cyclodextrin is also very low (about 22%).        
WO2014/125501 discloses the preparation of 6-per-deoxy-6-per-chloro-γ-cyclodextrin by chlorination of γ-cyclodextrin with a halogenating agent, prepared from phosphorous pentachloride and dimethylformamide. After completion of the chlorination, the mixture is quenched with water. The obtained mixture is hydrolyzed with aqueous sodium hydroxide solution, filtered, washed repeatedly with water and dried to give 6-per-deoxy-6-per-chloro-γ-cyclodextrin.
The process disclosed in WO2014/125501A1 suffers from the following disadvantages:                (i) The halogenating agent, which is prepared by reaction of phosphorous pentachloride and dimethylformamide, produces numerous phosphorous species on reaction with dimethylformamide, and its subsequent use for the halogenation of γ-cyclodextrin also produces phosphate esters as impurities which are difficult to remove.        (ii) The filtration of 6-per-deoxy-6-per-chloro-γ-cyclodextrin is very challenging as it takes very long time for the filtration due to its amorphous nature.        (iii) The purity of 6-per-deoxy-6-per-chloro-γ-cyclodextrin is also very low (about 23%).        
Thus, the prior art procedures for the preparation of 6-per-deoxy-6-per-chloro-γ-cyclodextrin suffer from the following disadvantages outlined below;                (i) The use of phosphorus based reagents for the halogenation of γ-cyclodextrin. The reagent produces unwanted impurities as by product which is very difficult to remove and require multiple purifications.        (ii) The handling of highly viscous reaction mixture of 6-per-deoxy-6-per-chloro-γ-cyclodextrin is very difficult.        (iii) The filtration of 6-per-deoxy-6-per-chloro-γ-cyclodextrin is also very challenging due to its amorphous nature.        
USPTO Backgrounds
USPTO Backgrounds