期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 25, 期 50, 页码 11641-11645出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201903267
关键词
C-H metalation; flow chemistry; ibuprofen; reaction optimization; superbase
资金
- National Research Foundation (NRF) of Korea - Korean government [NRF-2017R1A3B1023598]
Ibuprofen was prepared from an inactive and inexpensive p-xylene by three-step flow functionalizations through chemoselective metalations of benzyl positions in sequence using an in situ generated LICKOR-type superbase. The flow approach in the microreactor facilitated the comprehensive exploration of over 100 conditions in the first-step reaction by varying concentrations, temperatures, solvents, and equivalents of reagents, enabling optimal conditions to be found with 95 % yield by significantly suppressing the formation of byproducts, followed by the second C-H metalation step in 95 % yield. Moreover, gram-scale synthesis of ibuprofen in the final step was achieved by biphasic flow reaction of solution-phase intermediate with CO2, isolating 2.3 g for 10 min of operation time.
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