核化学与放射化学2025，Vol.47Issue(1)：93-102,10.DOI:10.7538/hhx.2025.47.01.0093
放射性同位素14C标记瑞德西韦的合成
Synthesis of Radioisotope 14C Labelled Remdesivir
摘要
Abstract
To prepare the radiotracer for the pharmacokinetics study of Remdesivir,the 14C labelled Remdesivir at 4-C in pyrrolo[2,1-f][1,2,4]triazine moiety was synthesized via ten-step reaction.Firstly,nonradioactive lH-pyrrole was formylated with N,N-dimethyl[14C]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 tetrahydro furan 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[4-14C]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 14C labelled Remdesivir(compound 2b,2-ethylbutyl N-[({[(2R,3S,4R,5R)-5-(4-amino[4-14C]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 HPLC-FSA.Its technical data(radiochemical/chemical purity＞98％,specific activity 2 069.8 MBq/mmol,content of radioactive/nonradioactive single impurity＜1％)was determined by TLC-IIA,HPLC-LSC,HPLC-FSA/PDA/MS,LSC,and HPLC-MS/MS.The following tracing study indicates that the target product can be used as radiotracer in the radiopharmacokinetics study of Remdesivir.关键词
同位素标记合成/瑞德西韦/14C/放射性示踪剂/抗病毒剂Key words
isotopically labelled synthesis/Remdesivir/14C/radiotracer/antiviral agent分类
能源科技引用本文复制引用
余志扬,杨征敏,李梦雪,宋明钰,周兵,秦雨馨,李书琰..放射性同位素14C标记瑞德西韦的合成[J].核化学与放射化学,2025,47(1):93-102,10.基金项目
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) （NO.201905-FX-H25-095）
