氟苯尼考特定有关物质的合成

Synthesis of Specific Related Substances of Florfenicol

本研究首次报道了欧洲药典收录的氟苯尼考2个二聚体杂质的合成方法,以(4S,5R)-4-甲酰基-2,2-二甲基-5-[4-(甲磺酰基)苯基]唑烷-3-碳酸叔丁酯和3-取代(R=—OH,F)的(1R,2R)-2-氨基-1-[4-(甲磺酰基)苯基]-1-丙醇为起始原料,经还原胺化、脱保护和酰胺化即可得到2,2-二氯-N-[3-[1,3-二羟基-1-[4-(甲磺酰基)苯基]丙-2-基]氨基]-1-羟基-1-[4-(甲磺酰基)苯基]丙基乙酰胺(1a,欧洲药典有关物质C)和2,2-二氯-N-[3-[3-氟-1-羟基-1-[4-(甲磺酰基)苯基]丙-2-基]氨基]-1-羟基-1-[4-(甲磺酰基)苯基]丙基乙酰胺(1b,欧洲药典有关物质D)。产物结构经1H NMR、^(13)C NMR和HRMS确证,可用于氟苯尼考产品的质量研究。

The synthesis of two dimeric related substances of florfenicol recorded in the European pharmacopoeia was firstly reported.With tert-butyl(4S,5R)-4-formyl-2,2-dimethyl-5-[4-(methylsulfonyl)phenyl]oxazolidine-3-carboxylate and 3-substituted(R=—OH,F)(1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]propan-1-ol as starting materials,2,2-dichloro-N-[3-[1,3-dihydroxy-1-[4-(methylsulfonyl)phenyl]propan-2-yl]amino]-1-hydroxy-1-[[4-(methylsulfonyl)phenyl]propan-2-yl]acetamide(1a,related substance C)and 2,2-dichloro-N-[3-[3-fluoro-1-hydroxy-[4-(methylsulfonyl)phenyl]propan-2-yl]amino]-1-hydroxy-1-[[4-(methylsulfonyl)phenyl]propan-2-yl]acetamide(1b,related substance D)were obtained by reductive amination,deprotection and amidation.The structures of the target compounds were confirmed by 1H NMR,^(13)C NMR and HRMS.