A new method for large-scale production of Boc-protected 4-fluoro L-proline

In 2020, OPRD reported a large-scale production method of Boc-protected 4-fluoro L-proline
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First, the first step is the classic deoxyfluorination
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In order to remove and eliminate by-products, the article investigates several existing methods: 1) column purification, although simple and straightforward, but time-consuming, labor-intensive and inefficient; 2) deprotection, reduction, hydrolysis, crystallization and reprotection, this strategy The route is lengthy, the molecular utilization rate is low, and it also involves the reduction of precious metals, and the cost is high; 3) Hydrolysis, cyclohexylamine salt formation and crystallization and then dissociation, the route is relatively short, but the operation is still relatively difficult, and the process of dissociation requires precise control of Ph; 4) The last one, after hydrolysis, olefin and hypochlorous acid are added (or oxidized) and then washed with water to remove the addition (or oxidation) by-products, but the use of oxides will have certain safety risks
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All of the above methods have their own shortcomings, and none of them can meet the requirements of safety, high efficiency, and simple route in actual production
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Finally, by studying the physical properties of 1 and 9, it is found that the product 1 can precipitate crystals in the hot toluene solution, while the by-product 9 shows good solubility
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