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Initial Scale–up and Process Improvements for the Preparation of a Lead Antibacterial Macrolone Compound

Objective

  • Modification of a 13-step route to a lead compound
  • Development of a synthetic procedure suitable for the preparation of several hundred gram quantities with at least 98% purity

Challenge

  • To prepare sufficient material to support preclinical in vivo studies within limited time frame

Modified synthetic procedure was successfully applied using laboratory 5 L reactor to prepare an initial 350 g of lead compound.

Synthetic route to lead compound and key building blocks

Synthesis of a key intermediate

Minor modifications in the workup, isolation and purification were required to furnish 2.0 kg of intermediate 6 in 66% overall yield with >99.5% purity

Optimised synthetic route - multigram scale synthesis

Summary

  • Critical reaction steps in the medicinal chemistry route were modified for an initial scale up process.
  • Synthetic procedure for several hundred gram quantities of the final product with over 98% purity was developed.
  • The new procedure does not require any purification by column chromatography.
  • Total of 350 g of lead compound was prepared.

References

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