Development of Flow Chemistry Techniques: Resolution of Problematic Industrial Process Chemistry Reactions

天然产物的类似物被认为是一个丰富的药物相关化合物的储存库，许多这样的分子被商业化用于治疗有用的药物，如癌症治疗。历史上，有机化学领域的大量努力已经应用于开发新的合成方法来构建这些天然产物及其相应的治疗有用的衍生物。尽管已经开发了许多合成转化，但迫切需要新的合成方法来使合成更短、更安全、更绿色和更原子经济。本研究项目的目标是通过创建新的基于流动化学的方法来解决道尔顿药物服务公司已经确定的有问题的过程化学反应，该方法将用于活性药物成分（API）的合成，这些活性药物成分通常是天然产物的衍生物。具体而言，我们将开发新的基于流动的合成方案，用于i）使用氢化铝锂（LiAlH4）的还原和ii）将炔还原为适合于工艺规模应用的烯烃。目前，这些类型的反应由于间歇化学反应固有的安全性和反应性问题而在大规模进行时特别成问题。为了解决这些问题，我们将开发流动化学合成方案，以取代目前的工艺规模分批方法（见下文）。流动化学领域有望对有机合成学科产生变革性的影响，它避免了昂贵、低效的分批方法，取而代之的是更安全、更环保、更熟练的化学转化的上级方法。在其最简单的形式中，流动化学用流动微反应器取代了传统的固定体积的间歇反应烧瓶，因此称为“流动”化学。该研究项目计划利用流动化学的好处，开发连续流动工艺，以解决这些间歇反应放大时所固有的问题。总的来说，解决了道尔顿制药服务公司发现的有问题的批量反应，并产生了更具成本效益和更安全的化学工艺。

Analogues of natural products are known to be an abundant reservoir for medicinally relevant compounds, withmany such molecules being commercialized into therapeutically useful drugs, such as cancer therapies.Historically, considerable effort in the field of organic chemistry has been applied to the development of newsynthetic methods for the construction of these natural products and their respective therapeutically usefulderivatives. Although many synthetic transformations have been developed, new synthetic methods areurgently required to make syntheses shorter, safer, greener and more atom economical. It is the goal of thisresearch project to resolve problematic process chemistry reactions that have been identified by Dalton PharmaServices by creating new flow chemistry-based methods that will be used in the synthesis of activepharmaceutical ingredients (API), which are commonly derivatives of natural products. Specifically, we willdevelop new flow-based synthesis protocols for i) reductions using lithium aluminum hydride (LiAlH4) and ii)reduction of alkynes to alkenes that are suitable for process scale applications. Currently, these types ofreactions are particularly problematic to perform on large scale due to safety and reactivity problems that areinherent to batch chemistry reactions. To solve these issues, we will develop flow chemistry synthetic protocolsthat will replace these current process scale batch methods (vide infra). The field of flow chemistry is poised tohave a transformative effect on the discipline of organic synthesis by avoiding the costly, inefficient methods ofbatch, and replacing them with superior methods that allow for safer, greener and more proficient chemicaltransformations. In its simplest form, flow chemistry replaces conventional fixed-volume batch reaction flaskswith flow microreactors, hence the term "flow" chemistry. This research project plans to utilize the benefits offlow chemistry and develop continuous flow processes that will solve the problems that are inherent whenscaling-up these batch reactions. Overall, resolving the problematic batch reactions that have been identified byDalton Pharma Services, and yield much more cost-effective and safer chemical processes.