Last. Chunjie Zhao(SPU: Shenyang Pharmaceutical University)H-Index: 6
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An efficient synthesis process of an antiepileptic drug, lacosamide, with high chiral purity has been developed. A series of acids were screened to form salts with the key intermediate 4, and phosphoric acid, an inexpensive and achiral reagent, turned out to be the best counterion, which could enhance both chemical purity and chiral purity of the key intermediate 4. 4-Phosphate was used for the successful synthesis of lacosamide with high chemical and chiral purities.
An improved synthesis of Lacosamide 1 with high purity has been developed. Critical parameters of each step were identified as well as the impurities generated. Moreover, a creative method to improve chiral purity and stability of the key intermediate (R)-2-amino-N-benzyl-3-methoxypropionamide 10 by forming salt with an achiral acid (phosphoric acid) was discovered to ensure the chiral purity of (R)-Lacosamide. Phosphoric acid was further developed for the deprotection of the Boc group.
An efficient and scalable synthesis of 7-amino-3-methylisobenzofuran-1(3H)-one (1) and 2-amino-6-ethylbenzoic acid (2) has been developed via a one-step catalytic hydrogenation. The triethylammonium salt of 2-acetyl-6-nitrobenzoic acid was used as the starting material and 1 was prepared in a biphasic solvent system of toluene/H2O, while 2 was obtained when the solvent was replaced with H2O. Intermediates 1 and 2 could be used to synthesize Pyriftalid and Paquinimod, respectively.