Steiner Alexander, Nelson Ryan C, Dallinger Doris, Kappe C Oliver
Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria.
Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria.
Org Process Res Dev. 2022 Aug 19;26(8):2532-2539. doi: 10.1021/acs.oprd.2c00214. Epub 2022 Aug 4.
A procedure for the continuous flow generation of thiomorpholine in a two-step telescoped format was developed. The key step was the photochemical thiol-ene reaction of cysteamine hydrochloride and vinyl chloride as low-cost starting materials. This reaction could be conducted under highly concentrated (4 M) conditions using a low amount (0.1-0.5 mol %) of 9-fluorenone as the photocatalyst, leading to the corresponding half-mustard intermediate in quantitative yield. Thiomorpholine was subsequently obtained by base-mediated cyclization. The robustness of the process was demonstrated by performing the reaction for 7 h (40 min overall residence time), isolating the desired thiomorpholine via distillation.
开发了一种以两步串联形式连续流生成硫代吗啉的方法。关键步骤是以低成本的原料盐酸半胱胺和氯乙烯进行光化学硫醇-烯反应。该反应可以在高浓度（4 M）条件下，使用低量（0.1-0.5 mol%）的9-芴酮作为光催化剂进行，以定量产率得到相应的半芥子气中间体。随后通过碱介导的环化反应得到硫代吗啉。通过进行7小时的反应（总停留时间40分钟），并通过蒸馏分离出所需的硫代吗啉，证明了该工艺的稳健性。
