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<p>Continuous flow chemistry for organic synthesis is an emerging technique in academia and industry because of its exceptional heat and mass transfer ability and, in turn, higher productivity in smaller reactor volumes. Preparative electrospray (ES) is a technique that exploits reactions in charged microdroplets that seeks to accelerate chemical synthesis. In Chapter 2, the flow synthesis of atropine, a drug which is included in the WHO list of essential of medicines and currently in shortage according to the U.S Food and Drug Administration (FDA)is reported.The two steps of atropine synthesis were initially optimized separately and then continuously synthesized using two microfluidic chips under individually optimized condition.The telescoped continuous-flow microfluidics experiment gave a 55% conversion with an average of 34% yield in 8 min residence time. In Chapter 3, a robotic HTE technique to execute reactions in 96-well arrays was coupled with fast MS analysis. Palladium-catalyzed Suzuki-Miyaura (S-M) cross-coupling reactions were screened in this system and a heat map was generated to identify the best reaction condition for downstream scale up in continuous flow. <br></p><p><br></p><p>In Chapter 4, an inexpensive and rapid synthesis of an old anticancer drug, lomustine,was synthesized. Using only four inexpensive commercially available starting materials and a total residence time of 9 min, lomustine was prepared via a linear sequence of two chemical reactions performed separately in two telescoped flow reactors. Sequential offline extraction and filtration resulted in 63% overall yield of pure lomustine at a production rate of 110 mg/h. The primary advantage of this approach lies in the rapid manufacture of lomustine with two telescoped steps to avoid isolation and purification of a labile intermediate, thereby decreasing the production cost significantly. A high throughput reaction screening approach based on desorption electrospray ionization mass spectrometry (DESI-MS) is described in Chapter 4 and 5 for finding the heat-map from a set of reaction conditions. DESI-MS is used to quickly explore a large number of reaction conditions and guide the efficient translation of optimized conditions to continuous flow synthesis that potentially accelerate the process of reaction optimization and discovery. Chapter 5 described HTE ofSNAr reactions using DESI-MS and bulk techniques with 1536 unique reaction conditions explored using both in DESI-MS and bulk reactors. The hotspots from the HTE screening effort were validated using a microfluidic system that confirmed the conditions as true positives or true.<br></p>
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| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/8023475 |
| Date | 25 June 2020 |
| Creators | Zinia Jaman (6618998) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/thesis/HIGH_THROUGHPUT_EXPERIMENTATION_AS_A_GUIDE_TO_THE_CONTINUOUS_FLOW_SYNTHESIS_OF_ACTIVE_PHARMACEUTICAL_INGREDIENTS/8023475 |
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