期刊
ORGANIC PROCESS RESEARCH & DEVELOPMENT
卷 26, 期 9, 页码 2715-2727出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.oprd.2c00184
关键词
lorazepam; route design; continuous flow; telescoped flow synthesis; high throughput experimentation
资金
- Purdue University-Department of Chemistry
- SURF Fellowship
- DARPA [HR0011-20-C-0199]
- Purdue Center for Cancer Research grant CCSG [CA23168]
This article presents a novel 5-step continuous flow synthesis for lorazepam, a widely used sedative. Each step was optimized and translated to continuous flow, resulting in over 99% pure lorazepam.
Lorazepam, a widely used sedative that appears on the World Health Organization list of essential medicines, experiences periodic shortages. Using a workflow involving route scouting, high-throughput experimentation, and impurity profiling to develop an optimal sequence, we report a novel 5-step route for synthesis of lorazepam in flow. The five steps comprise N-acylation, diazepine ring closure, imine N-oxidation, Polonovski-type rearrangement, and ester hydrolysis to give lorazepam. Each step was optimized and translated to continuous flow. The mean residence times for each of the individual flow reactions summed to a total of 72.5 min for the 5-step sequence. We also report a comprehensive analysis of the purity and byproduct profile to maximize the desired product purity in each step, leading to over 99% pure lorazepam.
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