放射性同位素^(14)C标记瑞德西韦的合成  

Synthesis of Radioisotope ^(14)C Labelled Remdesivir

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作  者:余志扬[1] 杨征敏 李梦雪 宋明钰 周兵 秦雨馨 李书琰 YU Zhi-yang;YANG Zheng-min;LI Meng-xue;SONG Ming-yu;ZHOU Bing;QIN Yu-xin;LI Shu-yan(Institute of Nuclear Agricultural Sciences,Zhejiang University,Hangzhou 310058,China;Zhejiang Isotope Labelled Compounds Co.,Ltd.,Jiaxing 314303,China;Shanghai Qizhen Radiosynthesis Research Centre,Shanghai 201403,China)

机构地区:[1]浙江大学原子核农业科学研究所,浙江杭州310058 [2]浙江爱索拓标记医药科技有限公司,浙江嘉兴314303 [3]上海启甄同位素标记合成研究中心,上海201403

出  处:《核化学与放射化学》2025年第1期93-102,I0004,共11页Journal of Nuclear and Radiochemistry

基  金:上海张江国家自主创新示范区专项发展资金重点资助项目(NO.201905-FX-H25-095)。

摘  要:为制备瑞德西韦药代动力学研究所必需的放射性示踪剂,以N,N-二甲基[^(14)C]甲酰胺为同位素原料,经亲电取代、分子间环化、碘代、亲核加成、羟基保护等十步放射性反应,反相高效液相色谱(HPLC)纯化和手性HPLC拆分获得目标物(217.7 MBq,光学纯度(ee)>99%),总放化收率为4.3%。经核磁共振氢谱(1H NMR)、质谱(MS)和在线放射性高效液相色谱(HPLC-FSA)分析确认,目标物为[吡咯并三嗪环-4-^(14)C]瑞德西韦。放射性薄层成像分析(TLC-IIA)、离线放射性高效液相色谱分析(HPLC-LSC)、在线放射性高效液相色谱-二极管阵列检测器/质谱联用(HPLC-FSA/PDA/MS)、液体闪烁测量(LSC)和HPLC-MS/MS分析表明,所得标记物的放化纯度和化学纯度均大于98%,比活度为2069.8 MBq/mmol,放射性/非放射性单一杂质含量均小于1%,该标记物可作为示踪剂,用于瑞德西韦的放射性药代动力学等研究。To prepare the radiotracer for the pharmacokinetics study of Remdesivir,the ^(14)C labelled Remdesivir at 4-C in pyrrolo[2,1-f][1,2,4]triazine moiety was synthesized via ten-step reaction.Firstly,nonradioactive 1H-pyrrole was formylated with N,N-dimethyl[^(14)C]formamide and phosphorus oxychloride in dichloroethane at 0-15℃,followed by cyanidation with hydroxylamine in the solution of potassium hydroxide and amination with O-(2,4-dinitrophenyl)hydroxylamine in tetrahydrofuran at 0-15℃.The resulting product 5 was cyclized with formamidine acetate in the presence of tribasic potassium phosphate in EtOH at 78℃,and then iodinated with N-iodosuccinimide to obtain the key intermediate 7-iodo[4-^(14)C]pyrrolo[2,1-f][1,2,4]triazin-4-amine(compound 7-1)in DMF at 0℃.Secondly,the intermediate 7-1 was substituted by the nonradioactive intermediate 7-2 and then cyanided to achieve the intermediate 9 at-65--60℃.The protecting benzyls in intermediate 9 were deprotected with boron trichloride in dichloromethane at-65--60℃,and two secondary hydroxyls of the deprotected product were selectively protected with acetone in the presence of TsOH in 2,2-dimethoxypropane at 25℃.Thirdly,the resulting product 11-1 was phosphated with the nonradioactive intermediate 11-2 and tert-butylmagnesium chloride in tetrahydrofuran at 0-20℃,and then deprotected with acetic acid at 100℃to obtain the carbon-14 labelled product Remdesivir as racemic mixture 13.Finally,the target product ^(14)C labelled Remdesivir(compound 2b,2-ethylbutyl N-[({[(2R,3S,4R,5R)-5-(4-amino[4-^(14)C]pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydro-2-furyl]methyl}oxy)(oxo)(phenyloxy)-λ5-phosphanyl]-L-alaninate;217.7 MBq,optical ee>99%)was obtained in the ten-step chemical/radiochemical yield of 4.3%after the purification by using preparative RP-HPLC and resolution of the racemic mixture by using chiral semi-preparative HPLC.The product 2b was compared with the standard sample of nonradioactive Remdesivir and charactered by 1H NMR,ESI-MS,and

关 键 词:同位素标记合成 瑞德西韦 ^(14)C 放射性示踪剂 抗病毒剂 

分 类 号:TL923[核科学技术—核燃料循环与材料] O628.21[理学—有机化学] R914.5[理学—化学]

 

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