Pilot-Scale Continuous Production of LY2886721: Amide Formation and Reactive Crystallization

Abstract

The design, development, and implementation of a pilot-scale continuous Schotten−Baumann amide bond formation and reactive crystallization to afford LY2886721 is described. The material met all API quality attributes and was comparable to material produced by a defined batch process. The scalability of the reaction and crystallization processes was confirmed during the development process. The pilot-scale equipment set was contained in a walk-in fume hood and operated at a production rate of 3 kg/day in a 72 h continuous run. Significant technical and business drivers for running the process in continuous flow mode were proposed and examined during development. The continuous process provided for lab hood commercialization and provided for minimal material at risk in the process. The demonstration also confirmed the risk inherent to operation of a tubular reactor under supersaturated conditions, and fouling occurred in the plug flow reactor. Fouling also occurred in the crystallizer. Recognizing these deficiencies, the process operated within the footprint of a standard walk-in fume hood, providing a successful demonstration of the opportunities afforded by continuous processing for low volume pharmaceuticals.

Integrated Continuous Pharmaceutical Technologies—A Review

“…In the next paper they developed the synthesis of a drug candidate, LY2886721. 100 The system consisted of a flow chemical step and continuous reactive crystallization. In this study the authors presented the optimization of the processes, the scale-up and development of the equipment, and longer operational tests as well.…”

“…The entire system was integrated, and stable operation was achieved on a kilogram per a week production scale. In the next paper they developed the synthesis of a drug candidate, LY2886721 . The system consisted of a flow chemical step and continuous reactive crystallization.…”

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

“…Lowering the energy of the LUMO of the dienophile via the incorporation of a Lewis acid is a commonly employed strategy in catalysing such reactions. While the use of salts such as aluminium(III) chloride may pose solubility issues in flow, numerous methods for the continuous processing of reaction slurries have been reported [44,[428][429][430][431]. Alternative methods of catalysis have also been developed over the past few decades which offer feasible transposition to flow.…”

Practical Considerations and Examples in Adapting Amidations to Continuous Flow Processing in Early Development

“…While solid-phase-supported peptide synthesis via continuous processing has been well-documented in the literature, solution-phase flow amidations have been reported more sporadically. Polster and colleagues demonstrated a Schotten–Baumann reaction by coupling an acid chloride with an amine using a plug flow reactor (PFR) . A continuous stirred-tank reactor (CSTR) process for the scale-up of a highly potent drug candidate was described by White and co-workers from the same Eli Lilly process chemistry group .…”

“…Polster and colleagues demonstrated a Schotten−Baumann reaction by coupling an acid chloride with an amine using a plug flow reactor (PFR). 7 A continuous stirred-tank reactor (CSTR) process for the scaleup of a highly potent drug candidate was described by White and co-workers from the same Eli Lilly process chemistry group. 8 In the latter example, application of continuous process approaches showed clear benefits in reducing potential worker exposure by reducing the number of unit operations and allowing commercial-scale active pharmaceutical ingredient (API) production in laboratory fume hoods.…”