Conversion of the Laboratory Synthetic Route of the N-Aryl-2-benzothiazolamine R116010 to a Manufacturing Method

Abstract

A facile and large-scale preparation of the antitumor agent R116010 has been developed. The new synthetic process requires four steps: (i) Friedel−Crafts reaction of N-phenyl-2-benzothiazolamine with 2-chloropropionyl chloride, (ii) conversion of the α-chloroketone into the corresponding α-(dimethylamino)ketone and resolution of the latter, (iii) reduction of the chiral aminoketone with resultant formation of the β-amino alcohol and finally (iv) conversion of the amino alcohol into the β-aminoimidazole R116010. The key strategic improvement is the crystallization-induced diastereomeric dynamic resolution of the aminoketone, leading to the chiral ketone in 90% yield and 90% enantiomeric purity. This new process improves the overall yield from 0.26 to 18.8% without tedious chromatographic separations and hazardous reaction conditions.

Synthesis of 2‐Aminobenzothiazoles via Copper(I)‐Catalyzed Cross‐Coupling with Part‐Per‐Million Catalyst Loadings

“…The product 3a is an important intermediate for the preparation of the antitumor agent R116010. [12] It is worthy of mention that the residual copper content in the product 3a was 0.95 ppm (ICP analysis) after silica gel column chromatography and that this content well meets the pharmaceutical requirements. [13] …”

Design and synthesis of substituted imidazole and triazole N-phenylbenzo[d]oxazolamine inhibitors of retinoic acid metabolizing enzyme CYP26

“…Cyclisation of the isocyanate 3 to form the benzoxazole 4 was achieved by reaction with 2-aminophenol in the presence of mercury oxide and catalytic sulphur [22]. Introduction of the imidazole to give the required product 5 involved reaction with carbonyldiimidazole (CDI) and imidazole [23] with subsequent purification by column chromatography. The carboxylic acid 5d was obtained by saponification of the ester 5c using a 2M aq.…”

Prospective Teratology of Retinoic Acid Metabolic Blocking Agents (RAMBAs) and Loss of CYP26 Activity

“…7) [63][64][65]. Molecular docking studies of (S)-R115866 using a homology model of CYP26A1 [54] placed (S)-R115866 in the en- zyme active site with the triazole nitrogen perpendicular to the haem iron at a distance of 2.6 Å, an ideal distance for transition metal coordination.…”