Journal
ORGANIC PROCESS RESEARCH & DEVELOPMENT
Volume 24, Issue 6, Pages 1124-1130Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.oprd.0c00115
Keywords
prazole sulfide monooxygenase; esomeprazole; asymmetric oxidation; oxygen mass transfer; reaction regulation
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Funding
- National Natural Science Foundation of China [21922804, 21871085, 21536004]
- National Key R&D Program of China [2019YFA09005000]
- Fundamental Research Funds for Central Universities [22221818014]
- State Key Laboratory of Bioreactor Engineering
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Esomeprazole is the most popular proton pump inhibitor (PPI) for treating gastroesophageal reflux disease. Enzymatic asymmetric sulfoxidation is a green approach to produce chiral sulfoxides. In this report, we focused on optimizing asymmetric sulfoxidation catalyzed by prazole sulfide monooxygenase (AcPSMO). The costly redox cofactor NADPH utilized by AcPSMO was regenerated by formate dehydrogenase with CO2 as the coproduct, which can be removed easily. During the scale-up process, oxygen supply was found to be the main limiting factor during the early phase of the reaction, while the instability of AcPSMO and the lack of the cofactor NADPH hindered progress during the middle and late phases of the 0.6 L reaction. Finally, by adjusting oxygen mass transfer and increasing the dissolved oxygen, the enzymatic reaction was stepwise amplified to a 120 L scale using a 300 L thermostatic stirred reactor, affording 95.9% conversion and 99.9% enantiomeric excess after 12 h. Extraction and refinement of the product resulted in 0.39 kg of the isolated esomeprazole (sodium salt), with 57.8% overall yield (73.4% before the salt-forming reaction) and 99.1% purity. Thus, a green-by-design system was constructed for the efficient and precise oxidation of omeprazole sulfide into esomeprazole with molecular O-2 as the green cosubstrate and CO2 and H2O as byproducts.
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