CAJ | 학술논문

磷酸奥司他韦作为选择性的流感病毒神经氨酸酶抑制剂，是治疗禽流感最有效的药物．美国药典38版收载了磷酸奥司他韦中的两个杂质．杂质（3R ，4R ，5S ）-3-（1-乙基丙氧基）-4-乙酰胺-5-氨基-1-环己烯-1-羧酸（A ）是原料药在精制和存储过程中发生微量水解产生的．对合成条件进行了优化，采用了常规分离手段得到了杂质A ，合成收率达到86．6％．杂质3-羟基-4-乙酰氨基-苯甲酸乙酯（B ）是美国药典38版所载磷酸奥司他韦中的另一个杂质，目前没有合成方面的报道．设计了杂质B的合成路线，以3-羟基-4-氨基苯甲酸为原料，用乙酸酐作为酰化试剂对原料进行乙酰化，然后加入氢氧化钠和盐酸，调节pH ，发生水解，最后用溴乙烷作为烃化剂得到了目标产物，合成收率达到52．1％．整条合成路线操作简单、反应条件温和、没有环境污染，对磷酸奥司他韦的生产检验和贮存均具有现实意义．
린산오사타위작위선택성적류감병독신경안산매억제제，시치료금류감최유효적약물．미국약전38판수재료린산오사타위중적량개잡질．잡질（3R ，4R ，5S ）-3-（1-을기병양기）-4-을선알-5-안기-1-배기희-1-최산（A ）시원료약재정제화존저과정중발생미량수해산생적．대합성조건진행료우화，채용료상규분리수단득도료잡질A ，합성수솔체도86．6％．잡질3-간기-4-을선안기-분갑산을지（B ）시미국약전38판소재린산오사타위중적령일개잡질，목전몰유합성방면적보도．설계료잡질B적합성로선，이3-간기-4-안기분갑산위원료，용을산항작위선화시제대원료진행을선화，연후가입경양화납화염산，조절pH ，발생수해，최후용추을완작위경화제득도료목표산물，합성수솔체도52．1％．정조합성로선조작간단、반응조건온화、몰유배경오염，대린산오사타위적생산검험화저존균구유현실의의．
Oseltamivir phosphate as a potent selective neuraminidase inhibitor is the most effective treat-ment of avian influenza now. There are two related substances of Oseltamivir phosphate recorded in USP38. Impurity (3R, 4R, 5S )-4-acetamido-5-amino-3- (1-ethylpropoxy )-1-cyclohexene-1- carboxylic acid(A) is produced during the refining and storage of the raw material medicine. We optimized the synthesis process of A and got it with a 86. 6% yield by conventional separation methods. Impurity 4-Acetylamino-3-hydroxybenzoic acid ethyl ester(B)is the other related substance recorded, and there is no report about synthetic route of it so far. After exploring the references related to B, we proposed a synthesis process, using 3-hydroxy-4-amino benzoic acid as raw material and acetic anhydride as acyla-tion reagent, then adding sodium hydroxide and hydrochloric acid to regulate pH, sequently hydrolysis occurring. Finally we got B with a 52. 1% yield by bromoethane as alkylating agent. The entire syn-thetic route has the advantages of simple operation, mild reaction condition and no environmental pollu-tion, w hich has practical significance for the production, inspection and storage of Oseltamivir phos-phate.