Continuous Flow Synthesis of Methyl Oximino Acetoacetate: Accessing Greener Purification Methods with Inline Liquid–Liquid Extraction and Membrane Separation Technology

Abstract

A greener continuous flow procedure for the synthesis and purification of methyl oximino acetoacetate, a key intermediate for the generation of several heterocyclic scaffolds, has been established. The synthesis is based on the continuous flow generation of nitrous acid to effect the oximation reaction. Neat reactants and a nearly saturated aqueous NaNO 2 solution have provided a methodology with a very low solvent consumption. The extraction of the oxime from the reaction mixture, a challenging process due to the presence of acetic acid in the solution, has been achieved by liquid−liquid extraction in a microreactor and a continuous multistage phase separation platform. Fine-tuning of the output pH by inline monitoring using a flow cell has enabled optimal extraction performance as well as the minimization of the acetic acid residue in the organic phase and the use of very low amounts of extraction solvents. An excellent value for the process mass intensity of 11.1 has been achieved. Moreover, the lack of acetic acid in the product avoids an additional and energy-consuming distillation step.

Sulphonated graphene oxide catalyzed continuous flow synthesis of pyrazolo pyrimidinones, sildenafil and other PDE-5 inhibitors

“…Herein, we observed the sulphonated product 6 was obtained in 10 min, at ambient temperature with 88% yield (see the ESI, Table S3, † entry 4). As shown in (ESI Table S4 †), further to remove the excess amount of the chloro sulfonic acid which is present in the reaction medium and also to minimize the post-downstream purication process, we further appended continuous aqueous quenching, and dropletbased extraction strategy [32][33][34][35][36][37] (see the ESI; Fig. S8 and Table S4 †).…”

Multi‐Step Continuous‐Flow Organic Synthesis: Opportunities and Challenges

“…Kappea nd co-workers developed an in-line liquid-liquide xtractiona nd membranes eparation technology to obtain methylo ximino acetoacetate (Figure43), ak ey synthon of heterocyclic scaffolds. [45] In-line extraction and phase separation are crucial for the telescoped sequence. The reported technology's key features are:i ns itu generation of nitrous acid from inexpensive startingm aterials;l ow solvent consumption,a nd efficient flow extractiono ft he oxime.…”

“…Kappe and co‐workers developed an in‐line liquid–liquid extraction and membrane separation technology to obtain methyl oximino acetoacetate (Figure 43), a key synthon of heterocyclic scaffolds [45] . In‐line extraction and phase separation are crucial for the telescoped sequence.…”

Continuous extraction and concentration of secreted metabolites from engineered microbes using membrane technology

“…The implementation of a continuous separation module also allows recovery of the solvents to be recycled within the process without the need of additional process steps. Continuous liquid–liquid separation can be considered a low-cost, low-energy alternative to conventional separation techniques 21 .…”