Periodic Reporting for period 1 - ChemoEnz (Chemo-Enzymatic Manufacturing Routes to High- Value compounds)
Période du rapport: 2015-06-01 au 2017-05-31
The aim of this project is to bring together subject matter experts from the academic and non-academic sectors to develop a platform of “green” chemoenzymatic methods for the production of high value active pharmaceutical ingredients – both those currently on the market, and those in development pipelines of the Pharma industry. The partners will exemplify the use of the platform through its application in the production of 4 drugs currently on the market – namely Duloxetine, Atomexetine, Ramosetron and Paricalcitol. In order to achieve this objective the proposal brings together 3 partners Kelada Pharmachem/(organo catalysis)/ Cerbios Pharma(Biocatalysis), IC-CNR (Protein crystallography) with complementary skills. Chiral alcohols are used as key intermediates in the manufacture of many APIs (Duloxetine, Atomoxetine, Sitagliptin, etc are only representative “Blockbuster” examples).
In spite of the many scientific reports detailing various approaches available to small scale preparation of chiral alcohols, these species are manufactured in large scale primarily via (a) diasteroisomeric resolution (e.g. current industrial synthesis of Duloxetine and Atomoxetine); (b) reduction of ketones using Rh, Pd, Ru, Pt and expensive phosphines (e.g. current industrial synthesis of Ramosetron); (c) reduction of ketones using expensive chiral reagents (e.g. current industrial synthesis of Paricalcitol). The syntheses of abovementioned compounds are far from ideal. For example, the preparation of Atomoxetine and Duloxetine is very low yielding and produces large amounts of waste and requires the use of strong acids and bases. A large part of the waste generated arises from the necessity of manufacturing the alcohol required for their synthesis via diastereoisomeric resolution, which produces an unwanted 50% material to be discarded or recycled. The preparation of Ramosetron is also low yielding and yet involves the use of expensive catalysts. Paricalcitol is manufactured through a long (14 steps) synthesis in an overall 5-6% yield. Therefore the preparation of these species via a more efficient, green and cheap synthesis will impact significantly on the technical and economic side of drug manufacture. There is an opportunity to design an improved industrial synthesis for each of these 4 examples from both a technical and economic point of view. The last ten years have witnessed the development of many organocatalytic and chemoenzymatic processes as new green methodologies to prepare enantiopure compounds. In spite of terrific intellectual advances, the industrial application of these technologies is still scarce. In coming together as a consortium for this project, we have identified a set of organocatalytic and chemoenzymatic transformations that could be translated into a number of syntheses which are industrially exploitable. This project provides the means to do just that by developing a platform for the preparation of enantiopure alcohols, which are valuable synthetic intermediates used in the preparation of many pharmaceutical active ingredients (APIs). There is great demand for technologies that facilitate the preparation of these intermediates in a green and cost efficient manner. So even in the structure of the consortium there is a high degree of novelty, originality and innovative potential. From a technology perspective, the synthesis of chiral alcohols we propose to develop offers the following innovations and (technical and economic) advantages: (a) a unique organocatalytic process to prepare a broad range of enantiopure benzylic alcohols; (b) a new enzymatic process to prepare specific enantiopure benzylic alcohols; (c) it employs inexpensive reagents and catalysts that could be recycled; (d) it allows the preparation of benzylic alcohols in both (S) and (R) configuration thus underlining the generality of this methodology (i.e. not just applicable to Duloxetine and Atomoxetine etc) which can be also applied to deliver more efficient syntheses of APIs. Therefore, the originality of the synthetic platform will be immediately demonstrated by its application to the solution of outstanding synthetic problems whilst at the same time having sufficient generality to be more widely applicable to the synthesis of other drugs which have chiral alcohols as key intermediates.
In spite of the many scientific reports detailing various approaches available to small scale preparation of chiral alcohols, these species are manufactured in large scale primarily via (a) diasteroisomeric resolution (e.g. current industrial synthesis of Duloxetine and Atomoxetine); (b) reduction of ketones using Rh, Pd, Ru, Pt and expensive phosphines (e.g. current industrial synthesis of Ramosetron); (c) reduction of ketones using expensive chiral reagents (e.g. current industrial synthesis of Paricalcitol). The syntheses of abovementioned compounds are far from ideal. For example, the preparation of Atomoxetine and Duloxetine is very low yielding and produces large amounts of waste and requires the use of strong acids and bases. A large part of the waste generated arises from the necessity of manufacturing the alcohol required for their synthesis via diastereoisomeric resolution, which produces an unwanted 50% material to be discarded or recycled. The preparation of Ramosetron is also low yielding and yet involves the use of expensive catalysts. Paricalcitol is manufactured through a long (14 steps) synthesis in an overall 5-6% yield. Therefore the preparation of these species via a more efficient, green and cheap synthesis will impact significantly on the technical and economic side of drug manufacture. There is an opportunity to design an improved industrial synthesis for each of these 4 examples from both a technical and economic point of view. The last ten years have witnessed the development of many organocatalytic and chemoenzymatic processes as new green methodologies to prepare enantiopure compounds. In spite of terrific intellectual advances, the industrial application of these technologies is still scarce. In coming together as a consortium for this project, we have identified a set of organocatalytic and chemoenzymatic transformations that could be translated into a number of syntheses which are industrially exploitable. This project provides the means to do just that by developing a platform for the preparation of enantiopure alcohols, which are valuable synthetic intermediates used in the preparation of many pharmaceutical active ingredients (APIs). There is great demand for technologies that facilitate the preparation of these intermediates in a green and cost efficient manner. So even in the structure of the consortium there is a high degree of novelty, originality and innovative potential. From a technology perspective, the synthesis of chiral alcohols we propose to develop offers the following innovations and (technical and economic) advantages: (a) a unique organocatalytic process to prepare a broad range of enantiopure benzylic alcohols; (b) a new enzymatic process to prepare specific enantiopure benzylic alcohols; (c) it employs inexpensive reagents and catalysts that could be recycled; (d) it allows the preparation of benzylic alcohols in both (S) and (R) configuration thus underlining the generality of this methodology (i.e. not just applicable to Duloxetine and Atomoxetine etc) which can be also applied to deliver more efficient syntheses of APIs. Therefore, the originality of the synthetic platform will be immediately demonstrated by its application to the solution of outstanding synthetic problems whilst at the same time having sufficient generality to be more widely applicable to the synthesis of other drugs which have chiral alcohols as key intermediates.
From a technical standpoint the project has achieved a new synthesis of Paricalcitol that is exploiting a new reaction that constitutes a prototype for the development of other potential syntheses. Similarly, the study carried out on the preparation of Atomoxetine and Duloxetine disclosed a new platform technology that could be applied to the preparation of many other drugs and intermediates thereof. In addition the project has created an environment in which researchers through pursuing the technical project objectives, develop their careers by building upon their existing skills, facilitating them to acquire new skills and work practices and gaining multi- and inter-disciplinary and intersectoral expertise. Increased the mobility of researchers between industry and academia. Provided academics an opportunity to learn best-practice from the commercial sector and similarly to enable researchers in the commercial sector to gain first-hand experience of working in a cutting-edge research environment with world-leading scientists. Exploited complementary expertise in each of the consortium partners to deliver the technical objectives of this project whilst also building future research and commercial opportunities. The above knowledge sharing objectives have been achieved primarily through secondment of experienced and early stage researchers between consortium members. This enhanced further through the provision of a series of technical and general initiatives at both a consortium and local level designed to facilitate knowledge sharing on a collective basis across the lifetime of the project.
The project has met with the expectation of two SMEs in developing their new routes to paricalcitol (Cerbios) and Atomoxetine (Kelada). the short term impact of these is difficult to predict, however, this study will place Kelada and derbies in a prominent position as process developer and APIs producers. From an educational standpoint, This project henabled the maximum impact on immediate and long-term career prospects of the researchers – whether they pursue career paths in academia or the private sector or indeed if they decide to become entrepreneurs. This was realised through a coherent blend of (i) inter- and multi-disciplinary research and knowledge exchange achieved through international secondment with (ii) formal training in transferrable skills and competences. It thereby addresses key European policy objectives mentioned previously, including the Agenda for New Skills & Jobs which amongst other things cites the need to: Improve flexibility and security in the labour market (“flexicurity”); Equip people with the right skills for the jobs of today and tomorrw .Enhance geographical mobility throughout the EU; entrepreneurship, self-employment and innovation.