In-line separation of multicomponent reaction mixtures using a new semi-continuous supercritical fluid chromatography system

Abstract

A new bespoke semi-continuous parallel column supercritical fluid chromatography unit has been developed that solves the problem of effective separation of continuous, multicomponent reaction mixtures. It enables the rapid in-line separation of crude mixtures produced during batch and continuous flow reactions. It overcomes limitations inherent to other systems, enabling it to collect up to five individual fractions from mixtures with any number of constituent components, and adds new machinery to aid the modern synthetic chemist. The success of the system was exemplified using two Appel-type reactions, enabling the recovery of 81% of 1-bromoethylbenzene (with a first pass purity of 92%) and 89% of an intermediate to the anti-cancer drug candidate AZ82 (>99% purity) from batch mixtures. As a notable example, the system was also used in a telescoped flow process to separate an intermediate during the synthesis of isoniazid. In this case, the three-stage synthesis was operated at steady state for four hours during which time 96% recovery of the intermediate, isonicotinamide, was attained (with a purity of >99%).React. Chem. Eng., 2018, 3, 799-806 | 799This journal is

Towards 4th industrial revolution efficient and sustainable continuous flow manufacturing of active pharmaceutical ingredients

“…However, this can be achieved by final-product purification using techniques such as multicolumn chromatography catch-and-release chromatography, simulated moving bed (SMB), crystallisation, recrystallisation and centrifugal partition chromatography (CPC). 51,54–59 Adding to scalability concerns of some of these purification methodologies, these techniques have their drawbacks; crystallization and recrystallisation usually requires semi-batch processing, catch-and-release chromatography needs automated multiple columns switching and the SMB chromatography operation is technically complex and it uses expensive absorbents. 12,51,60 The application of various downstream continuous flow processing strategies examples are reviewed herein.…”

Application of reactor engineering concepts in continuous flow chemistry: a review

“…The process was then repeatedly reverse cycled ultimately affording a 91% recovery of 169 after 5 h. The Ley group in their efforts to purify more complex reaction matrices developed a semi-continuous supercritical fluid chromatography (SFC) system which notably allowed the isolation of material that did not elute either first or last and furthermore the group was able to successfully integrate the purification system between two discrete reactions (Scheme 50). 180 The system operated by allowing a crude reaction mixture to be continuously recirculated through the loading loops of four independent Rheodyne injection valves and each valve was in turn connected to a separate column housed in a heating oven. Switching a valve to its injection orientation allowed a SFC system to pump a sample of the crude mixture through the column whereafter a selection valve could be automated to allow the collection of up to five fractions.…”

“…Switching a valve to its injection orientation allowed a SFC system to pump a sample of the crude mixture through the column whereafter a selection valve could be automated to allow the collection of up to five fractions. 180 The use of super critical carbon dioxide necessitated the need to separate the reaction mixture or purified fractions from gaseous carbon dioxide at points where system depressurization occurred, as such cyclone separators were inserted within the crude reaction mixture circulating loop directly after the Rheodyne injection valves, and after each of the final selection valves. The system was automated in such a manner as to try stagger the injections between the Rheodyne valves to allow an almost constant output stream of material.…”

A tutored discourse on microcontrollers, single board computers and their applications to monitor and control chemical reactions

“…This simple arrangement was exploited in a recent report where 24 individual pieces of equipment were controlled to enable semi-continuous separation of flow streams by supercritical fluid chromatography. 28 When a new device is connected to a network, it is assigned an IP address automatically which is used to direct traffic accordingly. If your device is configured to act as a web server, it can respond to queries for information via standard HTTP (or HTTPS) ports (80 and 443 respectively).…”