Abstract
In this perspective article, the use of continuous flow synthesis to prepare advanced pharmaceutical intermediates in developing economies is highlighted. Case studies are presented to suggest that cost effective local manufacture of life saving drugs, may potentially be implemented to facilitate better access to drugs to the underprivileged.
Introduction
In recent years, much attention has been given to continuous-flow protocols and the advantages of flow chemistry are well documented by several reviews published in recent literature [1–7]. Interestingly, whereas major advances in science in general transfer from academia to industry, the continuous-flow technique made the inverse transition where industry needed support from academia in order to develop better equipment, protocols, etc.
It is, however, worth understanding where in the world the activities in this area are being undertaken. Regarding flow chemistry equipment suppliers, other than Amar (India) and Zaiput (USA), most companies are based in Europe. One of the reasons for this is that the European Union, through various funding programs, was very keen to develop innovative technology to improve the competitiveness of the chemical manufacturing industry in Europe, given that a significant number of companies have exported chemical manufacturing to India and China over the last 40 years. Interestingly, Asia reacted to this trend and they started implementing flow manufacturing.
Another challenge in Europe and America is that a lot of custom chemical manufacturers now have excess batch manufacturing capacity. As such, from a financial perspective, the driver is to better use their existing infrastructure rather than investing in new technology. In less developed countries, such as South Africa and Brazil as an example, there are very few chemical manufacturers and, as such, very little existing infrastructure. Consequently, if companies are interested in establishing capacity, they have the freedom to review what technology (batch or flow) is best from both a cost and performance perspective. However, at the end of the day, the question is always the same: can we do it in a competitive price against Asia market? In order to overcome these challenges, developing countries need to be smart on the choice of drug candidates for continuous-flow protocol focusing on small volume high value drugs. Generics, besides the huge market which will reach $30 billion dollars in Brazil (2017) for example, is in general high volume low price where the payback for continuous-flow investment is far from the eye's reach; however, there is still interest from a supply chain perspective in order to guarantee access to drugs.
Another important issue, which should be addressed, is the fact that, in most of these developing economies, the basic chemical industry, which supports manufacturing companies, is underdeveloped and in some cases scarce. The lack of support from chemical industries in house makes manufacturing companies in these countries dangerously bound, and sometimes dependent, to the Asia/Europe intermediates market. The dependence cited here has an incredible effect on the final manufacturing price but also on the choice of synthetic route. In this way, the choice of drug candidate for continuous manufacturing in developing economies is critical and should be based on different aspects:
- –high value molecules/markets;
- –volume of drug needed to attend the market;
- –molecules where the synthetic know-how is not yet establish in house;
- –availability of intermediates/starting materials;
- –number of steps translated to continuous manufacturing;
- –possibility to telescope the synthesis;
- –benefits obtained compared to the batch process;
- –multipurpose facilities.
A few additional comments should be added here in order to make clear, for those who are not used to developing economies market, why these aspects are so important. A few of them have already been cited on earlier paragraphs, but others deserve a few more lines of explanation. First, it is really hard to believe that, in the next 10 years, we will see chemical/pharmaceutical industry changing from batch to continuous manufacturing for well-established batch process in developing countries; this can be true for the downstream but not for the synthetic part. In this way, at least in developing economies, continuous manufacturing has the chance only with new molecules, where the synthetic/process know-how is not yet established in house. Depending on the viability of starting materials and intermediates, if continuous manufacturing has been chosen as an option, telescoping the synthesis can be a smart choice depending on the number of steps. For example, for some drugs, the amount of intermediate that can be imported is limited per year; any oscillation in the amount of drug sold can leave the market unattended, and telescoping the synthesis in house can give you the benefit of a better management of the market. Another issue is the fact that sometimes importing intermediates from Asia/Europe/US can have a delivery time of months.
Continuous-manufacturing plants are in general customized for specific chemical transformations, but in this case, where the final price and investments are limited, multipurpose facilities are preferable in order to maximize your range of options when possible. The benefits obtained from applying continuous manufacturing must be clear; otherwise, the decision makers of the chemical/pharmaceutical industry will act as a classical organic chemist and stay with the big round bottom flask.
Active pharmaceutical ingredients are synthesized in manufacturing plants and then shipped to other sites to be converted into a form that can be given to patients, such as tablets, drug solutions, or suspensions. This system offers little flexibility to respond to surges in demand and is susceptible to severe disruption if one of the plants has to shut down. Worldwide, a variety of companies such as Novartis, GSK, Lilly, Lonza, and others are investigating continuous manufacturing of new drug substances in order to reduce their manufacturing costs and to provide more robust ways of producing the desired molecules. This demand had an incredible effect on the development of new technology such as flow reactors, as well as phase separators and pumps, among others, where some companies have established a new business by designing their own reactor system, such as the Lonza FlowPlate® micro- and milli-reactors.
It is important to note that, besides the fact that the fine chemical community knows continuous manufacturing as an emerging technology, the petrochemical industry has been using this technology for many years (since the 1960s) with several examples of success. The main idea behind the continuous process on petrochemical industry was to “fit the equipment to the process and not the process to the equipment.” One important difference between the two chemistry sectors, which must be pointed out, is the scale. Large-scale operations on petrochemical industry are far larger than the ones from the fine chemical or Advanced pharmaceutical intermediate (API) industry.
The following sections summarize a few areas where such countries could benefit from local manufacturing using new technology.
Active Pharmaceutical Ingredients and Fine Chemistry Industry
The initiative led by Prof. Frank Gupton at Virginia Commonwealth University, in collaboration with the Bill & Melinda Gates Foundation, called Medicines for All, seeks cheaper and more efficient ways to manufacture drugs, particularly those needed to treat human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) in developing countries. A nice example presented by their group was the synthesis of the nicotinonitrile precursor of nevirapine (Scheme 1), a non-nucleoside reverse transcriptase inhibitor, for which demand will increase in the next 10 years [8]. The main idea behind their strategy was to start with very simple commodity chemicals, in order to make it feasible for developing economies.
Continuous-flow approach for nicotinonitrile precursor of nevirapine
Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00019
In Brazil, our group has been working on similar strategies in order to develop new protocols under the continuous-flow environment for the synthesis of APIs [9–11]. The goal of the project, named Medicines Without Borders, is to identify targets of primary importance for the public health system in Brazil and develop know-how on continuous-flow methodology, so it could be shared with industry (Scheme 2).
Active pharmaceutical ingredients synthesized on the Medicines Without Borders project in Brazil
Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00019
Most of the molecules presented in Scheme 2 were selected from essential medicines on a list made by the Minister of Health in Brazil and published annually. It means that the Brazilian government will buy and distribute free of charge the listed molecules on the public health system.
Our first attempt was the synthesis of atazanavir, an HIV drug, in collaboration with Kappe's group, our major partner on the Medicines Without Borders project. The main objective of the atazanavir synthesis was to develop a smart way to synthesize the chiral epoxide, because this intermediate is crucial for the synthesis of many other HIV related APIs (Scheme 3). In this way, the chloro ketone was obtained on a 3-step continuous protocol affording the desired product in high yield and purity, where the key step was the diazomethane reaction using the tube-in-tube technology followed by acidic quench [10].
Continuous-flow approach towards chloro ketone intermediate of atazanavir and darunavir among others
Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00019
Following this initial attempt, we have focused our efforts on the synthesis of atazanavir and darunavir side chains (Scheme 4). Both side chains must be coupled with the chloro ketone (presented in Scheme 3), bearing the stereochemistry after the reduction of the carbonyl inverse between atazanavir and darunavir. Here, we can highlight the efficient synthesis of darunavir side chain where a continuous-flow ozonolysis followed by NaBH4 reduction afforded the racemic alcohol in quantitative yields in very short reaction times [11].
Atazanavir and darunavir side chain continuous-flow protocol
Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00019
Based on the same idea used for the synthesis of the chloro ketone intermediate of atazanavir synthesis, recently, we have presented our approach on a continuous-flow protocol for the production of mepivacaine and its analogs (Scheme 5). The strategy based on amide formation followed by hydrogenation/alkylation procedure gives versatility to the process, since after the initial amide formation, this intermediate could lead to any of its analogs just by switching the alkyl partner on the next step [12].
Mepivacaine and analogs strategy
Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00019
The biotechnology industry presents a worse scenario than the fine chemical industry for low incoming countries. Again, the lack of competitors in this field can represent a very interesting business opportunity for the establishment of bioprocesses, especially on a continuous-flow environment. Based on this idea, we have been also working on the development of biocatalyzed reactions under continuous-flow conditions applied to the synthesis of important building blocks to the pharmaceutical industry. Synthesis of chiral amines is an important transformation, and our group has used two different approaches in order to produce chiral methylbenzylamines: dynamic kinetic resolution mediated by lipases and asymmetric synthesis mediated by transaminases (Scheme 6) [13].
Dynamic kinetic resolution and asymmetric synthesis mediated by enzymes
Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00019
Dynamic kinetic resolutions were developed as a semi-continuous protocol where ammonium formate is used as an in situ H2 generator, in combination with Pd/BaSO4 as racemization catalyst, leading to the desired product with high yield and excellent selectivities. The asymmetric synthesis towards chiral methylbenzylamine was performed under continuous-flow conditions by immobilizing a wild-type Vibrios fluviaris transaminase, leading to the chiral product with good yields and selectivity. In both cases, the use of continuous-flow environment has drastically reduced the reaction time by increasing the mass transfer and improved catalyst recyclability by compartmentalization with the packed bed reactor [13].
Recently, a continuous-flow biocatalyzed process was also developed for the synthesis of crizotinib intermediate (Scheme 7). The major advantage of this strategy was the change of the racemization catalyst from the very expensive Schvo catalyst to the use of vanadyl sulfate, leading to the desired chiral product in moderate yields [14].
Biocatalyzed continuous-flow approach towards an intermediate of crizotinib synthesis
Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00019
South Africa does not have batch manufacturing technology; if batch production was to be implemented, the whole infrastructure would have to be established. The fact the flow technology is now well established to produce products in higher yield, and in many cases at reduced cost, this is the vision of how the process would be implemented locally. We recently reported the first continuous-flow synthesis of lamivudine (Scheme 8), an antiretroviral drug used in the treatment of HIV/AIDS and hepatitis B. The key intermediate (5-acetoxy oxathiolane) was prepared by an integrated two-step continuous-flow process from L-menthyl glyoxalate hydrate in a single solvent, in 95% overall conversion. For the crucial glycosidation reaction, using pyridinium triflate as the catalyst, an improved conversion of 95% was obtained. The overall isolated yield of the desired isomer of lamivudine (40%) was improved in the flow synthesis compared to the batch process [15, 16].
Synthesis of lamivudine
Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00019
It should be noted that South Africa has recently established Ketlaphela as a state owned pharmaceutical company. In the first instance, the aim is to establish fully integrated manufacturing processes, focusing on the local production of antiretrovirals (ARVs), but, clearly, once the facility is established, the infrastructure could be used for many other products. A further point that needs attention is research capacity development, in order to train appropriate scientists in this area of science and technology; as such, it is critical for such projects to have academic partners in these niche areas.
In a more sophisticated project, funded by the Defense Advanced Research Projects Agency (DARPA), the Massachusetts Institute of Technology researchers built a much smaller, transportable device suitable for small scale synthesis of drug molecules [17]. Their new system can produce four drugs formulated as solutions or suspensions: Benadryl, lidocaine, Valium, and Prozac. Using this apparatus, the researchers can manufacture about 1000 doses of a given drug in 24 h.
Outlook
Microreactor technology, more recently branded flow chemistry, is an emerging technique that enables those working in research and development to rapidly screen reactions utilizing continuous flow, leading to the identification of reaction conditions that are suitable for use at a production level. Various case studies have demonstrated that the technology is more cost effective. As a result, the technology provides a paradigm shift that potentially enables developing countries to facilitate local manufacture; in the first instance, this could potentially enable the regional synthesis of drugs to enable the underprivileged better access to key medicines.
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