Manufacture of chiral amines using catalytic and flow processing methods

Chiral amines are important building blocks used in 40% of pharmaceutical products and 20% crop protection compounds
and are high value chemical intermediates. However, current methods of manufacture are inefficient, wasteful, and often
unsuitable for complex structures. In particular, a lack of good methods to make secondary and heterocyclic chiral amines
was identified by the collaborating end users. The usual processes employ enantiomer resolution (50% max yield), which
adds processing steps and costs. In fact, the ASC pharmaceutical roundtable has listed this class of reactions as one of the
most important to solve, and continuous processing as the No 1 target in the key green engineeing reseacrh areas. The
chiral amine processes have all been studied and published by Blacker and Xiao using batch processing but not in flow.
Separation of the catalyst and its cost within the processes have prevented industry adoption. These issues will be
overcome in the current project using the Cp-star catalysts in flow.
The Leeds team is responsible for the testing, process development and scale-up/out of up to 5 different processes to
make homochiral secondary or tertiary heterocyclic amines (WP2). The studies require solid supported catalysts (Cp-Star)
and ligands generated at Liverpool (WP1) and YPT (WP3) and Leeds will test these in flow process equipment already in
the iPRD process lab, or slurry reactors developed and transferred to Leeds by AMT (WP4). The starting materials and
analytical methods will be supplied by the collaborating end-user companies (AZ, Pfizer, Syngenta and Dr Reddys)(WP5)
and the process data Leeds generates on product quality, cost, productivity will be used to compare with existing poor
methods for chiral amine manufacture. The processes to make homochiral amines are: (a) asymmetric reductive amination
(catalyst being developed at Liverpool, Leeds can undertake scale-up if required); (b) asymmetric transfer hydrogenation;
(c) amine DKR by immobilised enzyme resolution, continuous product separation and Cp-star catalysed racemisationrecycle
(d) crystallisation induced asymmetric transformation involving chiral amine crystallisation and catalysed
racemisation of the mother liquors (e) redox-neutral amine alkylation using hydrogen borrowing enantioselectively alkylate
amines. The chiral amines required by industry are heterocyclic secondary and tertiary amines such as piperidine,
piperazine, pyrrolidies, indolines etc. Within the project the companies will supply real examples of each class of chiral
amine to illustrate the potential for this technology. The use of flow methodology facilitates screening of multiple
compounds.
The flow reactors that will be used are fixed and trickle bed, cascade CSTR and the novel slurry reactors that are being
designed by AMT and transferred to Leeds for evaluation in these systems. The reactors are all meso-scale which is
required to generate data suitable for scale-up to manufacture. The measurable outputs of the work are entantioselectivity,
conversion, yield, kinetics and reation rate, mass balance (ie green metrics eg process efficiency and waste), productivity,
manufacturing process cost prediction (raw material, operational and capital). This data will be compared with existing
processes to the same products to enable cost benefit analysis thereby achieve the main objective of this part of the
project.

This project aims to develop commercially-viable catalytic methods for continuous production of one of the most important
fine chemical, pharmaceutical and agrochemical products, chiral amines, through joint effort between manufacturers,
academia and end users, this project addresses two key areas of this TSB call, changing batch to continuous processes
and using novel catalysis, contributing to sustainable manufacturing for the process industry.
The project will impact on large companies involved in fine chemical, pharmaceutical and agrochemical manufacturing, as
well as SME's involved in supplying to this sector catalysts and chemical reactor technology. The project addresses a
market gap and involves specific companies that wish to collaborate with the academic partners that together are able to
address this business opportunity by forming a chiral amine supply chain.
By developing innovative catalytic technology, the project aims to reduce the costs of manufacturing complex organic
products and make more available chiral amine materials increasingly required in their production. This opens new
business opportunities for chiral amine suppliers and in turn the technology companies supplying them with catalysts and
equipment. Chiral amines are important building blocks used in 40% of pharmaceutical products and 20% crop protection
compounds and are high value chemical intermediates. However, current manufacturing methods are inefficient, wasteful,
and often unsuitable for complex structures.
The ability to make cheaper chiral amines will not only generate new business and create jobs for the fine chemical
suppliers, but will generate revenues and IP for the technology providers. Reducing manufacturing costs and environmental
impact at the large companies improves their competitiveness and contributes to their sustainability as important employers
in the chemical sector. In particular, the continuous chiral amine production methods will impact upon many companies that
manufacture these products in the UK and globally, and the catalysts and reactors will assist the growth of two SMEs.
The UK industry as well as academia will not only benefit from the exploitation and application of the technology delivered
by this project but will also gain from the knowledge generated and from training highly skilled personnel adept in catalyst
science, who are essential to maintain the vibrant, inventive research community that is essential to a knowledge-based
society/economy.