Skip to main content

Development and Application of a New Class of Halogenated Reagents to Commercially Valuable Targets

Periodic Reporting for period 2 - Halo (Development and Application of a New Class of Halogenated Reagents to Commercially Valuable Targets)

Reporting period: 2019-01-01 to 2020-12-31

The pharmaceutical industry is constantly looking for cost efficient or greener methods of production of active ingredients. These are exciting times for chemists willing to re-think and invent novel synthetic procedures for the manufacture of active ingredients. Many exclusivity patents are just expired or about to expire. Without exclusivity rights, the opportunities in the active ingredients market will be driven only by the cost of production. Thus, a simple and cost effective synthetic method should be regarded as a realistic business opportunity. In this context, the preparation of many pharmaceutical active ingredients (API), is often realised by using transition metals (Rh, Pd, Ru, Pt) and expensive reagents such as phosphines. These reagents are expensive and an alternative is required in view of the worrying rate at which these metals are depleted. It has been estimated that their depletion will exceed economic viability within a decade. Significantly, many of the above mentioned chiral bonds could be formed also via reagents that are cheaper and come from natural sources. For example some of these using quinidine, the bitter flavour used in tonic water, were invented in the Adamo laboratory in the Royal College of Surgeons in Ireland. However, the industrial applicability of these techniques would become economically viable if the catalysts could be recycled and reused. Therefore, while on the manufacture side there is an unmet need for new, cheap and metal free synthetic technology, on the academic side there are many chemical reactions which in their present state are not suitable for industrial application. The aim of the proposed work is to provide solutions to some of these outstanding issues (translation), delivering novel (and patentable) synthetic technology impactful to the field of drug manufacture. In particular, the Adamo group has discovered a new reaction that allows the preparation highly valuable chemical intermediates that will be expanded, via this project, into a platform for the preparation of the metal free preparation of drugs.

The industrial syntheses of Tolterodine and Ezetimibe, two important active pharmaceutical ingredients, are not ideal and more efficient strategies are required. For example, Tolterodine is manufactured via a process which final yeld is ca 20%. In addition the synthetic layout currently employed involves two steps that require long reaction times (typically 4-6 days) and specialised (high pressure) apparatus. Therefore it could be concluded that the current state of the art for the large scale manufacture of Tolterodine is low yielding and time consuming. The current method of production of Ezetimibe is equally problematic as it involves a starting material which synthesis requires six steps and involves the use of expensive Rh-phosphine. Hence the current manufacture involves many steps and requires the use of expensive and not recoverable reagents. In spite of terrific advances in the field of fluorination, the preparation of organic fluorides is still underdeveloped.

With the above in mind herein we propose to advance the state of the art by achieving the following clear objectives of this project which correspond to the Work Packages health with this period of reporting.

WP1: Development of a new synthesis of Tolterodine.
WP2: scale up of new synthesis of Tolterodine up to 20L
WP5: Exemplification of alkoxylation to prepare enantiopure benzylic alcohols API intermediates
WP6: Preparation of benzylic fluorides

WP3 and WP4 regarding the 1g scale synthesis of ezetimibe and their scale up could not be achieved.
As specified above we have achieved the following objectives:

1. We have developed a new synthesis of Tolterodine, which is described in detailed in the Technical report. this work will be published after scale up studies will be performed.
2. We have developed a new bromination reaction that allowed the preparation of enantiopure benzyl bromides. This part of the work has been submitted for publication and is currently under evaluation.
3. We have shown that benzylic fluorides can be prepared similarly. this part of work will be patented soon by RCSI and prof Adamo, prior to publication.
4. We have shown that benxylic alcohols can be prepared, although in low enantioselectivity for the moment.


Hence it can be concluded that objectives conytained in WPs 1, 5 and 6 were fully achieved.
The synthesis of Tolterodine we have developed through WP1 is highly yielding (ca 60%, i.e. three times more than the currently employed one). Hence, it is novel and provides an opportunity to prepare an important Active Pharmaceutical Ingredient in larger chemical yields. As that, the one herein developed potentially would impact society by providing a business opportunity and by reducing significantly the amount of side products/ discard. Scale up has indicated that Tolterodine an be manufactured via the proposed synthesis. However in view of the dropping of price of production, the commercial significance is debatable.

More importantly, the demonstration of fluorination and alkoxylation provided via WP5 and WP6 opened up a wide number of potentially relevant socio-economic impacts. Fluorination in particular will be pursued by RCSI in further basic research and commercialisation activities. A commercialisation case feasibility study run to assess the commercial viability of the fluorination chemistry (and its patentability) indicated a significant impact this chemistry would have on the Pharma and Fine Chemical producer sectors.
Image for Halo