Multikilogram Synthesis of 4-d-Erythronolactone via Batch and Continuous Processing

Abstract

The conversion of a batch process to continuous (flow) operation has been investigated. The manufacture of 4,d-erythronolactone at kilogram scale was used as an example. Fully continuous processing was found to be impracticable with the available plant because of the difficulty in carrying out a multiphase isolation step continuously, so hybrid batch–continuous options were explored. It was found that very little additional laboratory or process safety work other than that required for the batch process was required to develop the hybrid process. A hybrid process was chosen because of the difficulty caused by the precipitation of solid byproduct during the isolation stage. While the project was a technical success, the performance benefits of the hybrid process over the batch were not seen as commercially significant for this system.

Alkyne–Azide Cycloadditions with Copper Powder in a High‐Pressure Continuous‐Flow Reactor: High‐Temperature Conditions versus the Role of Additives

“…One of the most appealing advantages of flow processing is its inherent scalability, which means that, in CF production, the volume is given as a function of time and flow rate, whereas, in standard flask‐based (batch) processes, the output depends on the batch size 21b,d,e. The batch scale‐up of processes that involve unstable reactants, such as azides, can be dangerous, because the accumulation of high concentrations of these materials can give rise to an explosive hazard, whereas, in CF processes, this risk is minimized because the residence time in the active zone of the reactor is nicely controllable and the procedure remains simple and safe, even upon scale‐up.…”

Popular Synthetic Approaches To Pharmaceuticals

“…56 In addition, some types of reaction can be significantly improved by flow methods, such as photochemical 57 and high temperature 58 and pressure reactions. 59 The formation of solids is often cited as a problem for flow reactions, 60 particularly when the channels are small. 61 The use of an agitated reactor can alleviate some of these issues.…”

Integrated Platform at ICES Kilo-Lab for Process Quality by Design

“…To test the integrated platform, a kilo-scale four-phase hybrid processing of 4-DEL was implemented at the ICES Kilo-Lab, which involves (i) salt formation using Disoascorbic acid and sodium carbonate solutions, (ii) batch oxidation using hydrogen peroxide and (iii) continuous operation of salt formation and oxidation, and (iv) acidification using hydrochloric acid to induce ring closure [7]. It is geared towards developing new process research techniques and to solve problems of scale-up and manufacturing for the pharmaceutical and specialty chemicals industry sector.…”

“…As with all paradigm shifts, there are gaps and teething issues to overcome in changing the way pharmaceutical manufacturing is carried out [6]. with batch and continuous processing units) [7]. process chemistry development, process analytical chemistry, process engineering and design, multivariate chemometrics, chemical process systems and control engineering) and enabling technologies (e.g.…”