Background

Amines are essential building blocks in agrochemicals, detergents, fine, and specialty chemicals. For example, alkylated anilines and carbazoles are used as chromophores in the manufacture of organic light emitting diodes (OLED). Alkylated phenylenediamines are used as antioxidants in rubbers, and alkylated long chain fatty amines are used in personal care and lubrication products.

The global market for bulk amines is worth $13 B (2018) and includes: phenylenediamines, short chain alkyl amines, fatty amines, and C3-6 diamines. Moreover, the amine moiety is common in several drugs including Ibutilide, Terfenadine, Aripiprazole, Fluspirilene, and Difenidol to name a few.

The rapidly emerging trend towards decentralized manufacturing in pharmaceuticals and specialty chemicals along with the need to minimize batch-to-batch variations and reactor downtime promotes continuous manufacturing as the preferred method for amines production. Four conventional processes are used in the production of aliphatic amines on large scale: (1) amination of alcohols, (2) amination of alkyl halides, (3) reduction of nitrile compounds, and (4) reductive amination of carbonyl compounds.

Technology Overview

NC State inventors have developed a selective in-flow production of amines via the atom-efficient hydroaminomethylation (HAM) route through the addition of 2-F-4-methylbenzoicacid co-catalyst and the application of N-Xantphos as a ligand for rhodium catalyst.

The HAM reaction proceeds through three main steps in an autotandem fashion (1) hydroformylation, (2) condensation, and (3) enamine hydrogenation. Steps (1) and (3) are gas – liquid reactions and thus can potentially be accelerated by utilizing a multi-phase flow reactor. Step (2), on the other hand, is a slow, liquid phase reaction and limits the scope for the reaction to non-hindered amines even in batch.

Further Details

Intensified Hydroaminomethylation (HAM) in Flow

Schematic illustration of the flow chemistry platform utilized for in-flow HAM

This work was published in Nature Communications

Benefits

The developed flow chemistry strategy enables 50 times enhancement in the kinetics of amine production compared to a batch reactor with a state-of-the-art catalyst at comparable amine regioselectivities.

The intensified in-flow HAM synthetic route allows for the distributed production of active pharmaceutical ingredients, organic light emitting diode (OLED) precursors, and other specialty chemicals with the ability to switch from mono- and dialkylated primary amines and from tertiary amines to enamines on-the-fly.

The scope of the in-flow HAM includes cyclic and acyclic alkylamines, anilines, and morpholine. Internal and terminal alkenes as well as styrene can be used as alkylating agents.

Applications

This invention allows for improved production of amines, which are the essential building blocks in agrochemicals, detergents, fine, and specialty chemicals.

Opportunity

NC State is currently seeking industry partners or licensees for the commercialization of this technology.

Improved Production of Amines via Automated Flow Chemistry

IP Status

Seeking