A Robust and Scalable Process for the Synthesis of Substantially Pure Clarithromycin 9-(E)-Oxime with an Established Control of the (Z)-Isomer Impurity

Kiran Chaudhari; Anil Gohar; Stijn Claerhout; Rakesh Ganorkar

doi:10.1021/acsomega.2c08207

A Robust and Scalable Process for the Synthesis of Substantially Pure Clarithromycin 9-(E)-Oxime with an Established Control of the (Z)-Isomer Impurity

ACS Omega. 2023 Mar 6;8(11):10411-10418. doi: 10.1021/acsomega.2c08207. eCollection 2023 Mar 21.

Authors

Kiran Chaudhari¹, Anil Gohar¹, Stijn Claerhout², Rakesh Ganorkar¹

Affiliations

¹ Hikal Ltd, 3A and 3B International Biotech Park Phase II, Hinjewadi, Pune, Maharashtra 411057, India.
² Galapagos NV, Generaal De Wittelaan L11, A3, Mechelen 2800, Belgium.

Abstract

Controlling the isomeric impurity in a key raw material is always critical to achieve the corresponding pure isomer-free targeted active pharmaceutical ingredient (API) in downstream processing. Clarithromycin 9-(E)-oxime is the key raw material for the synthesis of the 9a-lactam macrolide, which is an interesting scaffold for the synthesis of several bioactive macrolides. Here demonstrated is a scalable process for the preparation of substantially pure clarithromycin 9-(E)-oxime, with less than 1.2% of the (Z)-isomer. The process does not involve a separate time-consuming purification by a crystallization operation to purge the undesired (Z)-oxime isomer. Further, the pure clarithromycin 9-(E)-oxime obtained was subjected to the Beckmann rearrangement, thereby converting it into the pure 9a-lactam scaffold. Additionally, a few other impurities were identified and controlled at each stage. The fine-tuned process was successfully up scaled to a multikilogram scale, enabling the large-scale manufacturing of potential APIs derived from this scaffold.