Continuous Manufacturing of Active Pharmaceutical Ingredients via Flow Technology

The present work describes the development of an improved synthesis of the pharmaceutically relevant building block 2-butylbenzofuran (BBF). The telescoped hybrid batch−flow process is composed of three steps and affords the final product in high yield and purity. The key cyclization step is performed in continuous mode with integrated workup: this approach is more efficient compared to the standard batch conditions. The high quality of the product makes crude BBF suitable to be used in the downstream process of production of amiodarone without purification. The optimization was realized using the Design of Experiments approach and afforded a sustainable process suitable for industrial application.

Section: Procedures Lab-scale Synthesis Of Methyl 2-(2-formylphenoxy)...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Telescoped Hybrid Batch–Flow Synthesis of 2-Butylbenzofuran

Dedè,

Ciancimino,

Danelli

et al. 2024

“…After decades when continuous flow (CF) processing has been an essential technology in petrochemical and bulk chemical industries, in recent years, it became a major focus for process development also in the pharmaceutical sector. The academic efforts in this area grew a lot as well as the number of patents applications from industrial R&D groups. − …”

Section: Introductionmentioning

confidence: 99%

Dimethyl Fumarate: Heterogeneous Catalysis for the Development of an Innovative Flow Synthesis

Dedè¹,

Piccolo²,

Vigo³

2021

The present work describes the development of an improved synthesis of the active pharmaceutical ingredient (API) dimethyl fumarate. The use of continuous flow technology and the newly developed methylation conditions solve some of the issues of previous commercial production strategies, e.g., reaching complete conversion and avoiding the formation of toxic impurities. The optimization was carried out using the design of experiment approach and afforded a very efficient, sustainable process, suitable for the industrial application.

“…Currently, continuous processing is one aspect within process intensification, which targets the reduction of equipment size, costs, energy consumption, solvent utilization, and waste generation . Microreactor technology is an actively studied platform aiming at implementing continuous processing, achieving process intensification and finally assisting in delivering sustainable processes for the production of APIs …”

Section: Introductionmentioning

confidence: 99%

Hydrogen Chloride Gas in Solvent-Free Continuous Conversion of Alcohols to Chlorides in Microflow

Borukhova

Noël

Hessel

2016

Self Cite

Chlorides represent a class of valuable intermediates that are utilized in the preparation of bulk and fine chemicals. An earlier milestone to convert bulk alcohols to corresponding chlorides was reached when hydrochloric acid was used instead of toxic and wasteful chlorinating agents. This paper presents the development of an intensified solvent-free continuous process by using hydrogen chloride gas only. The handling of corrosive hydrogen chloride became effortless when the operating platform was split into dry and wet zones. The dry zone is used to deliver gas and prevent corrosion, while the wet zone is used to carry out the chemical transformation. The use of gas instead of hydrochloric acid allowed a decrease in hydrogen chloride equivalents from 3 to 1.2. In 20 min residence time, full conversion of benzyl alcohol yielded 96wt% of benzyl chloride in the product stream. According to green chemistry and engineering principles, the developed process is of an exemplary type due to its truly continuous nature, no use of solvent and formation of water as a sole by-product.