An efficient and novel route to (3R)-3-aminoazepane (1) is described. The target is obtained with 99.92% purity, 99.2% ee in seven steps, and 46.2% overall yield. This improved method involves a practical biocatalytic transformation with ωtransaminase to establish the stereogenic center high efficiently as a key step. The developed process was scalable, cost-effective, with a simplified reaction workup, avoiding the use of expensive metal catalyst or chromatography, and commercially viable for the synthesis of 1.
A novel six-step synthesis of 7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-ol (1) is described.
Starting with 3,4-difloro-2-methylbenzoic acid and using diphenyl
disulfide as an ideal sulfur source effectively solve the problems
such as harsh reaction conditions, usage of smelly thiophenol, which
might restrict the known process from pilot plant application. Large-scale
applicability of this new route has been successfully demonstrated
on kilogram-scale production to afford 1 with 98.04%
purity in 75% overall yield. Meanwhile, the corresponding impurity
profile was thus studied in detail and well documented.
A highly efficient preparation of enantiomerically pure syn aryl β-hydroxy α-dibenzylamino esters is reported. The outcome was achieved via dynamic kinetic resolution and asymmetric transfer hydrogenation of aryl α-dibenzylamino β-keto esters. The desired products were obtained in high yields (up to 98%) with excellent diastereoselectivity (>20:1 dr) and enantioselectivity (up to >99% ee). Furthermore, this method was applied for the gram-scale preparation of droxidopa.
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